Alternative titles; symbols
HGNC Approved Gene Symbol: SNCA
SNOMEDCT: 312991009, 80098002; ICD10CM: G31.83; ICD9CM: 331.82;
Cytogenetic location: 4q22.1 Genomic coordinates (GRCh38): 4:89,724,099-89,838,304 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q22.1 | Dementia, Lewy body | 127750 | Autosomal dominant | 3 |
| Parkinson disease 1 | 168601 | Autosomal dominant | 3 | |
| Parkinson disease 4 | 605543 | Autosomal dominant | 3 |
Alpha-synuclein is a highly conserved protein that is abundant in neurons, especially presynaptic terminals. Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies (summary by Giasson et al., 2000).
A neuropathologic hallmark of Alzheimer disease (104300) is widespread amyloid deposition. Analyzing the entire amino acid sequence in an amyloid preparation, Ueda et al. (1993) found, in addition to the major A-beta fragment (104760), 2 unknown peptides. They raised antibodies against synthetic peptides using subsequences of the peptides. These antibodies immunostained amyloid in neuritic and diffuse plaques as well as vascular amyloid. Electron microscopic study demonstrated that the immunostaining was localized on amyloid fibrils. Ueda et al. (1993) isolated an apparently full-length cDNA encoding a 140-amino acid protein within which 2 previously unreported amyloid sequences were encoded in tandem in the mouse hydrophobic domain. They tentatively named the 35-amino acid peptide NAC (for non-A-beta component of AD amyloid) and its precursor NACP. Secondary structure predicted that the NAC peptide sequence has a strong tendency to form beta-structures consistent with its association with amyloid. NACP was detected as a protein of molecular mass 19,000 in the cytosolic fraction of brain homogenates and comigrated on immunoblots with NACP synthesized in E. coli from NACP cDNA. NACP mRNA was expressed principally in brain but also in low concentrations in all tissues examined except in liver.
Campion et al. (1995) found by a computer search of protein sequence databases that NACP is the human counterpart of rat synuclein (Maroteaux and Scheller, 1991), with which it shares 95% sequence homology. Rat synuclein is specifically expressed in brain and is associated with synaptosomal membranes in neurons.
Campion et al. (1995) cloned 3 alternatively spliced transcripts in lymphocytes derived from a normal subject. Beyer et al. (2008) noted that there are at least 3 SNCA mRNA transcript variants generated by alternative splicing: SNCA140, which is the whole and main transcript, and SNCA112 and SNCA126, which result from in-frame deletions of exons 3 and 5, respectively. They identified a fourth transcript, SNCA98, which lacks exons 3 and 5 and is expressed at varying levels specifically in fetal and adult human brain.
Jakes et al. (1994) identified 2 distinct synucleins in human brain, alpha-synuclein and beta-synuclein (602569). They suggested that there may be a family of synucleins.
Nakai et al. (2007) found expression of Snca in murine bone marrow, including in erythroblasts and megakaryocytes. Snca was also present in reticulocytes and circulating erythroid cells. However, Snca-null mice showed no hematologic abnormalities. A 20-kD monomer of SNCA was detected in human erythrocytes.
Touchman et al. (2001) determined that the SNCA gene contains 6 exons and spans about 117 kb. Using transient transfection of a luciferase reporter construct, they determined that a simple upstream repeat is required for normal expression of SNCA. A similar, but not identical, repeat is located in the promoter region of the mouse Snca gene.
Theillet et al. (2016) used nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy to derive atomic-resolution insights into the structure and dynamics of alpha-synuclein in different mammalian cell types. Theillet et al. (2016) showed that the disordered nature of monomeric alpha-synuclein is stably preserved in nonneuronal and neuronal cells. Under physiologic cell conditions, alpha-synuclein is amino-terminally acetylated and adopts conformations that are more compact than when in buffer, with residues of the aggregation-prone non-amyloid-beta component (NAC) region shielded from exposure to the cytoplasm, which presumably counteracts spontaneous aggregation. Theillet et al. (2016) concluded that their results established that different types of crowded intracellular environments do not inherently promote alpha-synuclein oligomerization and, more generally, that intrinsic structural disorder is sustainable in mammalian cells.
Shahnawaz et al. (2020) showed that the alpha-synuclein-protein misfolding cyclic amplification (PMCA) assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson disease (168600) and samples from patients with multiple system atrophy (MSA1; 146500), with an overall sensitivity of 95.4%. Shahnawaz et al. (2020) used a combination of biochemical, biophysical, and biologic methods to analyze the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson disease and multiple system atrophy. They also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggested that alpha-synuclein aggregates that are associated with Parkinson disease and multiple system atrophy corresponded to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA.
Hartz (2010) mapped the SNCA gene to chromosome 4q22.1 based on an alignment of the SNCA sequence (GenBank L36675) with the genomic sequence (GRCh37).
Campion et al. (1995) mapped the NACP/synuclein gene to chromosome 4. Chen et al. (1995) mapped the NACP gene to 4q21.3-q22 by PCR-based analysis of human/rodent hybrid cells and by fluorescence in situ hybridization (FISH). Shibasaki et al. (1995) isolated a cosmid clone containing the SNCA gene and mapped it to 4q21.3-q22 by FISH. Spillantini et al. (1995) also used PCR panels and fluorescence in situ hybridization to map the SNCA gene to human chromosome 4q21.
Touchman et al. (2001) mapped the mouse Snca gene to chromosome 6, between the genes for Atoh2 and Atoh1 (601461).
Jakes et al. (1994) used immunohistochemistry to show that alpha-synuclein is concentrated in presynaptic nerve terminals.
Engelender et al. (1999) identified a novel protein-interaction partner of alpha-synuclein, which they designated synphilin-1, encoded by the gene SNCAIP (603779). Synphilin-1 was present in many regions in brain, including substantia nigra. They found that alpha-synuclein interacts in vivo with synphilin-1 in neurons. Cotransfection of both proteins (but not control proteins) in HEK293 cells yielded cytoplasmic eosinophilic inclusions.
It has been shown that the ortholog of alpha-synuclein in the zebra finch, synelfin, may play a role in song learning (George et al., 1995).
In a brief review article, Goedert (1997) noted that alpha-synuclein contains 7 imperfect repeats of an 11-amino acid sequence, which may mediate multimerization. The A53T mutation (163890.0001) associated with familial Parkinson disease (PD; 168601) lies in a 9-amino acid segment which connects the fourth and fifth such repeat. Goedert (1997) speculated that alpha-synuclein may be a component of Lewy bodies, where it may undergo abnormal aggregation. Spillantini et al. (1997) reported that alpha-synuclein may be the major component of Lewy bodies associated with Parkinson disease. Alpha-synuclein was found associated with brainstem-type and cortical Lewy bodies in Parkinson disease and Lewy body dementia (127750).
Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress is implicated in the pathogenesis of some of these disorders. Giasson et al. (2000) used antibodies to specific nitrated tyrosine residues in alpha-synuclein to demonstrate extensive and widespread accumulation of nitrated alpha-synuclein in the signature inclusions of Parkinson disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer disease, and multiple system atrophy (MSA; 146500) brains. The authors also showed that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selected and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.
Xu et al. (2002) demonstrated that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in nondopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54-83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein (113508), which are elevated selectively in the substantia nigra in Parkinson disease. Thus, Xu et al. (2002) concluded that accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in Parkinson disease.
Alves Da Costa et al. (2002) demonstrated that wildtype mammalian SNCA is antiapoptotic when overexpressed in mouse neuronal cells. SNCA lowered basal and staurosporin-induced caspase-3 immunoreactivity and activity, and this was accompanied by a decrease in several other markers of apoptosis. The antiapoptotic effect was reversed by 6-hydroxydopamine, which triggered SNCA aggregation.
Lotharius and Brundin (2002) reviewed the literature on SNCA and suggested a possible role for this protein in vesicle recycling via its regulation of phospholipase D2 and its fatty acid-binding properties. They hypothesized that impaired neurotransmitter storage arising from SNCA mutations could lead to cytoplasmic accumulation of dopamine, resulting in breakdown of this labile neurotransmitter in the cytoplasm and promoting oxidative stress and metabolic dysfunction in the substantia nigra.
Giasson et al. (2003) showed that alpha-synuclein induces fibrillization of microtubule-associated protein tau (MAPT; 157140), and that coincubation of alpha-synuclein and tau synergistically promotes fibrillization of both proteins in vitro. In vivo studies of mice with an alpha-synuclein mutation or a tau mutation showed filamentous inclusions of both proteins, which are abundant neuronal proteins that normally adopt an unfolded conformation but polymerize into amyloid fibrils in disease. The findings suggested an interaction between alpha-synuclein and tau that drives the formation of pathologic inclusions in human neurodegenerative diseases.
Sharon et al. (2003) identified a cellular pool of highly soluble oligomers of alpha-synuclein in cultured mesencephalic neurons, normal mouse brain, and normal human brains. Exposure of cultured neurons to polyunsaturated fatty acids increased alpha-synuclein oligomer levels, whereas saturated fatty acids decreased them. Mice accumulated soluble oligomers with age, and human brains from patients with PD or dementia with Lewy bodies (DLB; 127750) had elevated amounts of the soluble, lipid-dependent oligomers. Sharon et al. (2003) concluded that alpha-synuclein interacts with polyunsaturated fatty acids in vivo to promote the formation of soluble oligomers that precede the formation of insoluble alpha-synuclein aggregates associated with neurodegenerative disorders.
Outeiro and Lindquist (2003) observed that when expressed in yeast, alpha-synuclein associated with the plasma membrane in a highly selective manner, before forming cytoplasmic inclusions through a concentration-dependent, nucleated process. Alpha-synuclein inhibited phospholipase D, induced lipid droplet accumulation, and affected vesicle trafficking. Outeiro and Lindquist (2003) concluded that their readily manipulable system provided an opportunity to dissect the molecular pathways underlying normal alpha-synuclein biology and the pathogenic consequences of its misfolding.
Willingham et al. (2003) performed genomewide screens in yeast to identify genes that enhance the toxicity of a mutant huntingtin fragment or of alpha-synuclein. Of 4,850 haploid mutants containing deletions of nonessential genes, 52 were identified that were sensitive to a mutant huntingtin fragment, 86 that were sensitive to alpha-synuclein, and only 1 mutant that was sensitive to both. Genes that enhanced toxicity of the mutant huntingtin fragment clustered in the functionally related cellular processes of response to stress, protein folding, and ubiquitin-dependent protein catabolism, whereas genes that modified alpha-synuclein toxicity clustered in the processes of lipid metabolism and vesicle-mediated transport. Genes with human orthologs were overrepresented in their screens, suggesting that they may have discovered conserved and nonoverlapping sets of cell-autonomous genes and pathways that are relevant to Huntington disease (143100) and Parkinson disease (see 168600).
Iwata et al. (2003) found that the serine protease neurosin (KLK6; 602652) degraded alpha-synuclein and colocalized with pathologic inclusions such as Lewy bodies and glial cytoplasmic inclusions. In cell lysates, neurosin prevented alpha-synuclein polymerization by reducing the amount of monomer and also by generating fragmented alpha-synucleins that themselves inhibited the polymerization. Upon cellular stress, neurosin was released from mitochondria to the cytosol, which resulted in the increase of degraded alpha-synuclein species. Downregulation of neurosin caused accumulation of alpha-synuclein within cultured cells. The authors concluded that neurosin may play a significant role in physiologic alpha-synuclein degradation and also in the pathogenesis of synucleinopathies.
Cuervo et al. (2004) found that wildtype alpha-synuclein is selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic A53T (163890.0001) and A30P (163890.0002) alpha-synuclein mutants bound to LAMP2A (309060), the receptor for this pathway, but appeared to act as uptake blockers inhibiting both their own degradation and that of other substrates. Cuervo et al. (2004) suggested that these findings may underlie the toxic gain of function by the alpha-synuclein mutants.
Martinez et al. (2003) used a photocross-linking approach to show that alpha-synuclein binds to calmodulin (114180) in bovine brain cells. Further analysis showed that the binding occurred in a calcium-dependent manner with the mutant A53T protein as well as with the wildtype protein, and that calmodulin accelerated the formation of synuclein fibrils in vitro.
Using several related experiments, Liu et al. (2004) demonstrated that alpha-synuclein was associated with potentiation of synaptic transmission in cultured rodent hippocampal cells. Application of glutamate increased alpha-synuclein immunoreactivity and functional bouton number in the presynaptic terminal. Glutamate and tetanic application also resulted in increased spontaneous and evoked postsynaptic currents, but these effects were not seen in cultured hippocampal cells from Snca-null mice. Presynaptic injection of alpha-synuclein increased neurotransmitter release via production of nitric oxide. Liu et al. (2004) concluded that alpha-synuclein is involved in synaptic plasticity by augmenting transmitter release from the presynaptic terminal.
Cooper et al. (2006) found that the earliest defect following alpha-synuclein expression in yeast was a block in endoplasmic reticulum-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphate Ypt1p, which associated with cytoplasmic alpha-synuclein inclusions. Elevated expression of Rab1 (179508), the mammalian Ypt1 homolog, protected against alpha-synuclein-induced dopaminergic neuron loss in animal models of Parkinson disease. Thus, Cooper et al. (2006) concluded that synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
Using mass spectrometry analysis and immunohistochemistry, Fujiwara et al. (2002) showed that the ser129 residue of alpha-synuclein is selectively and extensively phosphorylated in synucleinopathy lesions. In vitro, phosphorylation at ser129 promoted insoluble fibril formation that likely contributes to the pathogenesis of neurodegenerative disorders.
Using detailed biochemical studies, Anderson et al. (2006) found that the predominant form of alpha-synuclein within Lewy bodies isolated from brains of patients with Lewy body dementia, multiple system atrophy, and PARK1 was phosphorylated at ser129. A much smaller amount of ser129-phosphorylated alpha-synuclein was found in the soluble fraction of both control and diseased brains, suggesting that ser129-phosphorylated alpha-synuclein shifts from the cytosol to be deposited in Lewy bodies, and that phosphorylation enhances inclusion formation. Other unusual biochemical characteristics of alpha-synuclein in Lewy bodies included ubiquitination and the presence of several C-terminally truncated alpha-synuclein species.
Outeiro et al. (2007) identified a potent inhibitor of sirtuin-2 (SIRT2; 604480) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. The inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson disease (PD; 168600). Outeiro et al. (2007) concluded that their results suggest a link between neurodegeneration and aging.
Beyer et al. (2008) demonstrated overexpression of SNCA112 in brains of patients with Lewy body dementia. SNCA98 expression was increased in brains from patients with DLB, Parkinson disease, and Alzheimer disease compared to controls. Beyer et al. (2008) postulated that differentially spliced SNCA isoforms may have different aggregation properties, which may be important in neurodegeneration.
The RING-type E3 ubiquitin ligase SIAH1 (602212) is present in Lewy bodies of the substantia nigra of Parkinson disease patients (Liani et al., 2004). Using immunofluorescence analysis, Lee et al. (2008) found that endogenous Siah1 and alpha-synuclein partially colocalized in cell bodies and neuritic processes of rat PC12 cells and mouse cortical neurons. Pull-down assays and coimmunoprecipitation analysis showed that rat Siah1 and alpha-synuclein interacted in vitro and in vivo. Using transfected HeLa cells, Lee et al. (2008) found that rat Siah1 bound the human brain-enriched E2 ubiquitin-conjugating enzyme UBCH8 (UBE2L6; 603890) and facilitated mono- and diubiquitination of alpha-synuclein in vivo. Ubiquitination of alpha-synuclein by Siah1 was disrupted by the A30P mutation of alpha-synuclein, but not by the A53T mutation. Studies in transfected HeLa and PC12 cells showed that Siah1-mediated ubiquitination did not target alpha-synuclein for proteasomal degradation, but rather promoted alpha-synuclein aggregation and enhanced its neurotoxicity.
Scherzer et al. (2008) found high SNCA expression in normal red blood cells during the terminal steps of erythrocyte differentiation, including reticulocytes. SNCA was strongly coexpressed and coinduced with critical enzymes of heme metabolism, including ALAS2 (301300), FECH (612386), and BLVRB (600941). Using this information, Scherzer et al. (2008) determined that expression of the SNCA gene in reticulocytes was regulated by the transcription factor GATA1 (305371), which specifically occupied a conserved region within intron 1 of the SNCA gene and could induce a 6.9-fold increase in alpha-synuclein protein. Endogenous GATA2 (137295), which is highly expressed in substantia nigra, also occupied intron 1 of the SNCA gene and modulated SNCA expression in dopaminergic cells.
Zucchelli et al. (2010) found that TRAF6 (602355) bound misfolded mutant DJ1 (PARK7; 602533) and SNCA, and that both proteins were substrates of TRAF6 ligase activity in vivo. Rather than conventional lys63 (K63) assembly, TRAF6 promoted atypical ubiquitin linkage formation to both Parkinson disease targets that shared K6-, K27- and K29- mediated ubiquitination. TRAF6 stimulated the accumulation of insoluble and polyubiquitinated mutant DJ1 into cytoplasmic aggregates. In human postmortem brains of Parkinson disease patients, TRAF6 protein colocalized with SNCA in Lewy bodies. The authors proposed a novel role for TRAF6 and for atypical ubiquitination in Parkinson disease pathogenesis.
Burre et al. (2010) showed that maintenance of continuous presynaptic SNARE complex assembly requires a nonclassical chaperone activity mediated by synucleins. Specifically, alpha-synuclein directly bound to the SNARE protein synaptobrevin-2/vesicle-associated membrane protein-2 (VAMP2; 185881) and promoted SNARE complex assembly. Moreover, triple-knockout mice lacking synucleins developed age-dependent neurologic impairments, exhibited decreased SNARE complex assembly, and died prematurely. Thus, Burre et al. (2010) concluded that synucleins may function to sustain normal SNARE complex assembly in a presynaptic terminal during aging.
Bartels et al. (2011) reported that endogenous alpha-synuclein isolated and analyzed under nondenaturing conditions from neuronal and nonneuronal cell lines, brain tissue, and living human cells occurs in large part as a folded tetramer of about 58 kD. Several methods, including analytical ultracentrifugation, scanning transmission electron microscopy, and in vitro cell crosslinking confirmed the occurrence of the tetramer. Native cell-derived alpha-synuclein showed alpha-helical structure without lipid addition and had much greater lipid-binding capacity than the recombinant alpha-synuclein studied theretofore. Whereas recombinantly expressed monomers aggregated into amyloid-like fibrils in vitro, native human tetramers readily underwent little or no amyloid-like aggregation. On the basis of their findings, Bartels et al. (2011) proposed that destabilization of the helically folded tetramer precedes alpha-synuclein misfolding and aggregation in Parkinson disease and other human synucleinopathies, and that small molecules that stabilize the physiologic tetramer could reduce alpha-synuclein pathogenicity.
Nakamura et al. (2011) found that overexpression of wildtype human SNCA, but not other synucleins, in HeLa cells and other cell lines caused mitochondrial fragmentation. SNCA overexpression also caused a mild disruption of Golgi, but had no effect on other organelles. Disruption of mitochondria in COS cells was followed by loss of mitochondrial membrane potential, formation of reactive oxygen species, disrupted oxygen consumption and respiration, and apoptotic cell death. Similar changes were observed in transgenic mice and cultured hippocampal neurons expressing human SNCA. Mitochondrial fragmentation required association of SNCA with mitochondrial membranes and depended upon SNCA N-terminal threonines. Incubation with artificial membranes showed that SNCA specifically interacted with the acidic phospholipid cardiolipin, which is enriched in mitochondria, and reduced the size of membranes containing cardiolipin. The SNCA mutants A53T and glu46 to lys (E46K; 163890.0004) bound mitochondrial membranes and caused mitochondrial fragmentation upon overexpression, whereas the A30P SNCA mutant did not bind mitochondrial membranes and did not cause mitochondria fragmentation.
Loss-of-function mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase, or GBA; 606463) lead to lysosomal accumulation of its substrate, glucosylceramide (GlcCer), and result in different forms of Gaucher disease (GD; see 230800), some of which include features of PD. Mazzulli et al. (2011) found that postmortem brains of patients with GD and features of PD, as well as mouse models of GD, showed neuronal accumulation of SNCA. Functional loss of GCase and resultant GlcCer accumulation in cultured mouse cortical neurons and human neurons reprogrammed from induced pluripotent stem cells resulted in compromised lysosomal degradation of long-lived proteins, including SNCA. Elevated cellular GlcCer also promoted SNCA aggregation. SNCA accumulation in turn inhibited normal lysosomal GCase activity in neurons and PD brain. In apparently normal human cortical samples, SNCA protein content, particularly high molecular mass species, correlated inversely with GCase activity. Mazzulli et al. (2011) hypothesized that a positive-feedback loop between defective SNCA and/or GCase could lead to self-propagating neurodegeneration over time.
Luk et al. (2012) found that in wildtype nontransgenic mice, a single intrastriatal inoculation of synthetic alpha-synuclein fibrils led to the cell-to-cell transmission of pathologic alpha-synuclein and Parkinson-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus established a mechanistic link between transmission of pathologic alpha-synuclein and the cardinal features of Parkinson disease.
Peelaerts et al. (2015) demonstrated that alpha-synuclein strain conformation and seeding propensity lead to distinct histopathologic and behavioral phenotypes. The authors assessed the properties of structurally well-defined alpha-synuclein assemblies (oligomers, ribbons, and fibrils) after injection in rat brain and showed that alpha-synuclein strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathologic phenotype displaying Parkinson disease and multiple system atrophy traits. Additionally, Peelaerts et al. (2015) showed that alpha-synuclein assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. These results demonstrated that distinct alpha-synuclein strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.
Brenner et al. (2015) identified 11 putative binding sites for GATA2, 4 for CEBPB (189965), and 2 for ZSCAN21 (601261) in the promoter region of the human SNCA gene. Chromatin immunoprecipitation (ChIP) analysis and EMSA of human brain nuclear extracts confirmed highly specific binding of GATA2 to a specific region within SNCA intron 2, and of ZSCAN21 to a single region within SNCA intron 1.
Dermentzaki et al. (2016) found that knockdown of Zscan21 resulted in upregulation Snca mRNA and protein in rat primary neuronal cultures. ChIP and immunoprecipitation analysis showed that Zscan21 was recruited to intron 1 of the Snca gene in rat cortical neuronal cultures. Overexpression of Zscan21 in rat cortical neuronal cultures led to robust Zscan21 mRNA expression but negligible protein expression, and consequently had little effect on Snca expression. Knockdown of Zscan21 in adult rat hippocampus in vivo had no detectable effect on Snca expression.
Mao et al. (2016) demonstrated that lymphocyte-activation gene-3 (LAG3; 153337) binds alpha-synuclein preformed fibrils (PFF) with high affinity (dissociation constant of 77 nanomolar), whereas the alpha-alpha-synuclein monomer exhibited minimal binding. Binding of alpha-alpha-synuclein-biotin to LAG3 initiated alpha-synuclein PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed alpha-synuclein PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. Mao et al. (2016) concluded that the identification of LAG3 as a receptor that binds alpha-synuclein PFF provided a target for developing therapeutics designed to slow the progression of Parkinson disease (PD; 168600) and related alpha-synucleinopathies.
Using an unbiased screen targeting endogenous gene expression, Mittal et al. (2017) discovered that the beta-2-adrenoreceptor (B2AR; 109690) is a regulator of SNCA. B2AR ligands modulate SNCA transcription through histone H3 lysine-27 acetylation (H3K27ac) of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the B2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a B2AR antagonist, propanolol, correlated with increased risk. B2AR activation protected model mice and patient-derived cells. Thus, Mittal et al. (2017) concluded that B2AR is linked to transcription of alpha-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.
Using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, Fusco et al. (2017) identified the fundamental characteristics that enable toxic alpha-synuclein oligomers to perturb biologic membranes and disrupt cellular function. These include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, Fusco et al. (2017) found that mutations that target the region that promotes strong membrane interactions by alpha-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.
In Lewy body diseases, including Parkinson disease with or without dementia (see 168600), dementia with Lewy bodies (127750), and Alzheimer disease with Lewy body copathology (see 127750), alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy (146500) alpha-synuclein accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs). Peng et al. (2018) reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. Peng et al. (2018) found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments.
Kam et al. (2018) found that pathologic alpha-synuclein activates PARP1 (173870), and poly ADP-ribose (PAR) generation accelerates the formation of pathologic alpha-synuclein, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP1 prevented pathologic alpha-synuclein toxicity. In a feed-forward loop, PAR converted pathologic alpha-synuclein to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with Parkinson disease, suggesting that PARP activation plays a role in Parkinson disease pathogenesis.
Using purified recombinant proteins, Panicker et al. (2019) showed that human FYN (137025) and CD36 (173510) mediated alpha-synuclein uptake in microglia. Immunohistochemical analysis revealed increased microgliosis and increased FYN expression and activation within microglia in brains of alpha-synuclein-overexpressing mice and in patients with PD. Uptake of alpha-synuclein in microglia induced mitochondrial dysfunction and generation of mitochondrial reactive oxygen species. Aggregated alpha-synuclein primed and activated the NLRP3 (606416) inflammasome through PKC-delta (PRKCD; 176977)-mediated NF-kappa-B (see 164011) activation, resulting in diminished production of IL1-beta (IL1B1; 147720) and other proinflammatory cytokines. The authors validated the in vitro findings in a mouse model of PD, as Fyn contributed to microgliosis and microglial inflammasome activation in vivo.
Burmann et al. (2020) systematically characterized the interaction of molecular chaperones with alpha-synuclein in vitro as well as in cells at the atomic level, and found that 6 highly divergent molecular chaperones commonly recognize a canonical motif in alpha-synuclein, consisting of the N terminus and a segment around tyr39, and hinder the aggregation of alpha-synuclein. NMR experiments in cells showed that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between alpha-synuclein and the chaperone HSC70 (600816) and members of the HSP90 family, including HSP90-beta (191175), resulted in transient membrane binding and triggered a remarkable relocalization of alpha-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of alpha-synuclein at tyr39 directly impaired the interaction of alpha-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase (ABL1; 189980) in Parkinson disease.
Interaction With Parkin
Shimura et al. (2001) hypothesized that alpha-synuclein and parkin (602544) interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive Parkinson disease (600116). Shimura et al. (2001) identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UBCH7 (603721) as its associated E2 ubiquitin-conjugating enzyme, and a novel 22-kD glycosylated form of alpha-synuclein (alpha-Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive Parkinson disease failed to bind alpha-Sp22. In an in vitro ubiquitination assay, alpha-Sp22 was modified by normal, but not mutant, parkin into polyubiquitinated, high molecular weight species. Accordingly, alpha-Sp22 accumulated in a nonubiquitinated form in parkin-deficient Parkinson disease brains. Shimura et al. (2001) concluded that alpha-Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathologic accumulation of alpha-Sp22. These findings demonstrated a critical biochemical reaction between the 2 Parkinson disease-linked gene products and suggested that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional Parkinson disease.
Chung et al. (2001) showed that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein synphilin-1 (603779). Coexpression of alpha-synuclein, synphilin-1, and parkin resulted in the formation of Lewy body-like ubiquitin-positive cytosolic inclusions. They further showed that familial mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. Chung et al. (2001) concluded that their results provided a molecular basis for the ubiquitination of Lewy body-associated proteins and linked parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.
Petrucelli et al. (2002) found that overexpression of mutant alpha-synuclein in human neuroblastoma cells resulted in impaired proteasome activity, resulting in decreased cell viability. Mutant alpha-synuclein was selectively toxic to tyrosine hydroxylase (TH; 191290)-positive neurons from the mouse midbrain, but not to TH-negative midbrain neurons or hippocampal neurons. Wildtype parkin was able to rescue the toxic effect of proteasome inhibition or mutant alpha-synuclein, but mutant parkin was not protective. The findings showed that both the parkin and SNCA genes alter the ability of neurons to tolerate reduced proteasome activity, indicating a common pathway in selective neurodegeneration in PD.
In neuroblastoma cells, Kawahara et al. (2008) found that in the presence of proteasomal inhibition, SNCA promoted the accumulation of insoluble parkin as well as insoluble alpha-tubulin (see, e.g., TUBA1A, 602529). Immunoblot analysis of brain samples from patients with Lewy body dementia showed increased levels of insoluble parkin and alpha-tubulin. Coimmunoprecipitation studies indicated that parkin and SNCA colocalized, particularly in the presence of a proteasomal inhibitor. Overexpression of SNCA resulted in decreased parkin and alpha-tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. The findings suggested that accumulation of alpha-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which, in turn, might compromise neural function by damaging the neuronal cytoskeleton.
Parkinson Disease and Lewy Body Dementia
Polymeropoulos et al. (1996) demonstrated that the Parkinson disease phenotype in a large family of Italian descent could be mapped to 4q21-q23. Designated Parkinson disease type 1 (PARK1; 168601), the disorder in this family was well documented to be typical for Parkinson disease, including Lewy bodies, with the exception of a relatively early age of onset of illness at 46 +/- 13 years. In this family, the penetrance of the gene was estimated to be 85%. Since the SNCA gene maps to the same region, it was considered an excellent candidate for the site of the mutation in PARK1. In the Italian family, Polymeropoulos et al. (1997) found a G-to-A transition in nucleotide 209 of the SNCA gene, which resulted in an ala53-to-thr substitution (A53T; 163890.0001). The same A53T mutation segregated with the Parkinson disease phenotype in 3 Greek kindreds. In these families also, the onset of the disease occurred relatively early.
Heintz and Zoghbi (1997) suggested that alpha-synuclein may provide a link between Parkinson disease and Alzheimer disease (104300), and possibly other neurodegenerative diseases.
Farrer et al. (1998) did not find mutations in the SNCA gene in 6 familial cases of autosomal dominant PD or 2 cases of amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam (105500). Scott et al. (1997) excluded linkage to alpha-synuclein in 94 multiplex (at least 2 sampled affecteds with Parkinson disease) families.
Scott et al. (1999) screened the translated exons of the SNCA gene for the A53T mutation in 356 affected individuals from 186 multiplex families with Parkinson disease. One Greek American family segregated this mutation as an autosomal dominant trait, giving a frequency for this mutation of 1 in 186, or 0.5%. The phenotype in this family was consistent with the other Greek and Italian families reported with this mutation. Other than autosomal dominant inheritance and wider intrafamilial variation in age at onset, there were no significant differences in the phenotype in this family and the other families in the data set. Members of the family remaining in Greece had been reported by Markopoulou et al. (1995). Scott et al. (1999) concluded that the SNCA gene is not a major risk factor in familial Parkinson disease.
In affected members of a Spanish family with autosomal dominant Lewy body dementia and parkinsonism (DLB; 127750), Zarranz et al. (2004) identified a point mutation in the SNCA gene (163890.0004).
Pals et al. (2004) reported evidence suggesting that SNCA promoter variability may contribute to susceptibility to PD. Among 175 Belgian PD patients, there was overrepresentation of minimum promoter haplotypes spanning approximately 15.3 kb. Specifically, the C-261-A-G-A-C and T-263-G-A-C-G haplotypes were found in 29% and 9% of patients compared to 20% and 3% of controls, respectively. The haplotypes encompassed the Rep1 promoter region but did not rely on Rep1 genotypes.
Alleles at NACP-Rep1, the polymorphic microsatellite repeat located approximately 10 kb upstream of the SNCA gene, were found to be associated with differing risks of sporadic Parkinson disease. Chiba-Falek and Nussbaum (2001) and Chiba-Falek et al. (2003) found that NACP-Rep1 acts as a negative modulator of SNCA transcription with an effect that varied 3-fold among different NACP-Rep1 alleles. Given that duplications and triplications of SNCA have been implicated in familial Parkinson disease, even a 1.5- to 2-fold increase in SNCA expression may, over many decades, contribute to PD. Chiba-Falek et al. (2005) identified factors that bind to NACP-Rep1 and potentially contribute to SNCA transcriptional modulation by pulling down proteins that bind to NACP-Rep1 and identifying them by mass spectrometry. One of the proteins was PARP1 (173870), a DNA-binding protein and transcriptional regulator. PARP1 binding to NACP-Rep1 specifically reduced the transcriptional activity of the SNCA promoter/enhancer in luciferase reporter assays. The association of different NACP-Rep1 alleles with Parkinson disease may be mediated, in part, by the effect of PARP1, as well as other factors, on SNCA expression.
Mueller et al. (2005) found no association between the SNCA promoter region, including the sequence repeat Rep1, and the development of PD among 669 German sporadic PD patients.
In a study of 557 PD patient-control pairs, Mamah et al. (2005) found that individuals with the SNCA Rep1 261/261 or MAPT H1/H1 genotypes had an increased risk of PD compared to those with neither genotype (odds ratio of 1.96); however, the combined effect of the 2 genotypes was the same as for either genotype alone. Mamah et al. (2005) suggested that the MAPT H1/H1 genotype may cause increased SNCA fibrillization in persons with lower SNCA protein concentrations due to genotypes other than Rep1 261/261. In persons with the Rep1 261/261 genotype, the MAPT H1/H1 genotype confers no additional risk because the SNCA protein is already at threshold concentration for self-fibrillization.
In a large study involving 2,692 PD patients from 11 different sites, Maraganore et al. (2006) found that the 263-bp Rep1 allele was associated with an increased risk of Parkinson disease (odds ratio of 1.43). The 259-bp Rep1 allele was associated with a reduced risk of PD (OR of 0.86). Genotypes defined by Rep1 alleles did not influence age at disease onset.
Among 659 PD patients, Goris et al. (2007) found a synergistic interaction between the MAPT H1 haplotype and an A-to-G SNP (rs356219) in the 3-prime region of the SNCA gene. Carrying the combination of risk genotypes at both loci approximately doubled the risk of disease (p = 3 x 10(-6)). The findings suggested that MAPT and SNCA are involved in shared or converging pathogenic pathways and may have a synergistic effect. Cognitive decline and the development of dementia was associated with the H1/H1 genotype (p = 10(-4)). In a final analysis that combined data from other studies, Goris et al. (2007) confirmed the association of the H1/H1 genotype with PD (odds ratio of 1.4; p = 2 x 10(-19)).
In a statistical analysis of 5,302 PD patients and 4,161 controls from 15 sites, Elbaz et al. (2011) found no evidence for an interactive effect between the H1 haplotype in the MAPT gene and SNPs in the SNCA gene on disease. Variation in each gene was associated with PD risk, indicating independent effects.
Multiple System Atrophy
See 146500 for a discussion of a possible association between variation in the SNCA gene and multiple system atrophy (MSA).
SNCA Gene Duplication/Triplication
In affected members of 3 unrelated families, 2 French and 1 Italian, with classic autosomal dominant Parkinson disease, Ibanez et al. (2004) and Chartier-Harlin et al. (2004) identified heterozygosity for whole-gene duplication of the SNCA gene (163890.0005).
In a large family with parkinsonism (PARK4; 605543) reported by Waters and Miller (1994), Singleton et al. (2003) found evidence consistent with triplication of the SNCA gene (163890.0003). The triplicated region contains an estimated 17 genes, including SNCA. Johnson et al. (2004) did not find SNCA multiplications in 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, or 366 healthy controls, and concluded it is a rare cause of disease. The patient cohort was white and Hispanic.
Ross et al. (2008) reviewed the clinical features and breakpoints involved in 5 previously reported families with either SNCA duplication (Chartier-Harlin et al., 2004, Fuchs et al., 2007, Nishioka et al., 2006) or SNCA triplication (Singleton et al., 2003, Farrer et al., 2004). The multiplications ranged in size from 0.4 Mb to 4.93-4.97 Mb, the latter of which encompassed 31 different gene transcripts. Microsatellite analysis indicated that SNCA genomic duplication resulted from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appeared to be required for genomic SNCA triplication. Although no single repeat was consistently observed at the breakpoints, a variety of Alu and LINE repeats were found at the breakpoints. A comparison of the phenotypes indicated that dosage of the SNCA gene, and not other genes in the region, specifically contribute to the variability in clinical observations among families, which ranged from classic Parkinson disease to Lewy body dementia with autonomic features. Increased SNCA gene dosage was associated with a more severe phenotype.
Ibanez et al. (2009) identified duplications of the SNCA gene in 4 (1.5%) of 264 mostly European families with typical PD. One (4.5%) of 22 families with atypical PD (PARK4), including rapid progression and severe cognitive impairment, was found to have triplication of the SNCA gene. Genotyping and dosage analysis indicated that SNCA multiplications occurred independently. There was a correlation between disease severity and SNCA copy number. The largest duplication was 4.50-5.29 Mb and included 33 to 34 genes, although the severity in this family did not differ from the other families. Ibanez et al. (2009) concluded that alterations in SNCA gene dosage due to rearrangements may be more common than point mutations.
Studies on Mutant Alpha-Synuclein Protein
Narhi et al. (1999) presented evidence related to the pathogenic mechanism of Parkinson disease caused by the 2 known mutants, ala30 to pro (A30P; 163890.0002) and A53T. They showed that both wildtype and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiologic temperature in vitro. Importantly, aggregate formation was accelerated by both Parkinson disease-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates was about 280 hours for the wildtype protein, 180 hours for the A30P mutant protein, and only 100 hours for the A53T mutant protein. These data suggested that the formation of alpha-synuclein aggregates could be a critical step in the pathogenesis of Parkinson disease, which is accelerated by the Parkinson disease-linked mutations.
Tabrizi et al. (2000) generated stable, inducible cell models expressing wildtype or Parkinson disease-associated mutant (209G-A; 163890.0001) alpha-synuclein in human-derived HEK293 cells. Increased expression of either wildtype or mutant alpha-synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha-synuclein induced a significant increase in sensitivity to dopamine toxicity compared with wildtype protein expression.
In an in vitro study, Conway et al. (2000) compared the rates of disappearance of monomeric alpha-synuclein and appearance of fibrillar alpha-synuclein for the wildtype and 2 mutant proteins, A53T and A30P, as well as equimolar mixtures that may model heterozygous Parkinson disease patients. Whereas A53T and an equimolar mixture of A53T and wildtype fibrillized more rapidly than wildtype alpha-synuclein, the A30P mutation and its corresponding equimolar mixture with wildtype fibrillized more slowly. However, under conditions that ultimately produced fibrils, the A30P monomer was consumed at a comparable rate or slightly more rapidly than the wildtype monomer, whereas A53T was consumed even more rapidly. The difference between these trends suggested the existence of nonfibrillar alpha-synuclein oligomers, some of which were separated from fibrillar and monomeric alpha-synuclein by sedimentation followed by gel-filtration chromatography. Conway et al. (2000) concluded that drug candidates that inhibit alpha-synuclein fibrillization but do not block its oligomerization could mimic the A30P mutation and may therefore accelerate disease progression.
Tanaka et al. (2001) created PC12 cell lines expressing mutant alpha-synuclein with the ala30-to-pro substitution (A30P; 163890.0002). These cells showed decreased proteasomal activity without direct toxicity and increased sensitivity to apoptotic cell death when treated with subtoxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 (600636) and caspase-9 (602234) and was blocked by cyclosporin A. The authors suggested that expression of mutant alpha-synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.
Lashuel et al. (2002) demonstrated that mutant amyloid proteins associated with familial Alzheimer and Parkinson diseases formed morphologically indistinguishable annular protofibrils that resemble a class of pore-forming bacterial toxins, suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases. The A30P (163890.0002) and A53T (163890.0001) alpha-synuclein mutations associated with Parkinson disease both promote protofibril formation in vitro relative to wildtype alpha-synuclein. Lashuel et al. (2002) examined the structural properties of A30P, A53T, and amyloid beta 'Arctic' (104760.0013) protofibrils for shared structural features that might be related to their toxicity. The protofibrils contained beta-sheet-rich oligomers comprising 20 to 25 alpha-synuclein molecules, which formed amyloid protofibrils with a pore-like morphology.
Mature alpha-synuclein is a small 14-kD protein with a central core region (residues 61-95) containing hydrophobic amino acids, known as the NAC region, that is responsible for fibril formation. Under physiologic conditions, alpha-synuclein is an unfolded protein with little or no ordered structure. Sode et al. (2005) found that a variant protein constructed with 2 hydrophilic residues replacing hydrophilic residues (val70thr/val71thr) retained the stable unfolded status better than the wildtype protein, and also prevented fibril formation when mixed with the wildtype protein or the mutant A53T protein.
Wildtype alpha-synuclein adopts several conformations that shield the amyloidogenic core region of the protein through long-range interactions between the N- and C- termini of the protein. Using nuclear magnetic resonance (NMR) spectroscopy to evaluate structural features, Bertoncini et al. (2005) found that mutant A53T and A30P alpha-synuclein proteins caused structural fluctuations that lost the native conformations and disrupted the autoinhibitory long-range interactions. The findings suggested that the mutations may foster self-association and fibril formation, resulting in a toxic gain of function.
Smith et al. (2005) generated A53T (163890.0001) mutant alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory system. Inducing expression of A53T alpha-synuclein in differentiated PC12 cells decreased proteasome activity, increased the intracellular reactive oxygen species (ROS) level, and caused up to 40% cell death, which was accompanied by mitochondrial cytochrome C release and elevation of caspase-9 and -3 activities. Cell death was partially blocked by cyclosporine A (an inhibitor of the mitochondrial permeability transition process), z-VAD (a pan-caspase inhibitor), and inhibitors of caspase-9 and -3. Furthermore, induction of A53T alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated caspase-12 (608633) activity. The authors concluded that both ER stress and mitochondrial dysfunction may contribute to A53T alpha-synuclein-induced cell death.
Using optical imaging with a pH-sensitive marker, Nemani et al. (2010) found that overexpression of SNCA inhibited synaptic vesicle exocytosis in cultured hippocampal neurons and in hippocampal slices from transgenic mice that overexpressed the SNCA gene. These transgenic mouse brains did not show SNCA-immunoreactive aggregates. The mechanism of decreased neurotransmitter release was determined to be a specific reduction in the size of the synaptic vesicle recycling pool. Ultrastructural analysis showed reduced synaptic vesicle density at the active zone, and imaging further revealed a defect in the reclustering of synaptic vesicles after endocytosis.
Alcohol Dependence
Bonsch et al. (2005) found an association between the length of the SNCA REP1 allele and alcohol dependence in 135 Caucasian alcoholic patients and 101 healthy Caucasian controls. The longer 273- and 271-bp alleles were more frequent in alcoholic patients compared to controls (p less than 0.001), and SNCA mRNA expression levels were correlated with the longer SNCA REP1 alleles.
Abeliovich et al. (2000) developed mice homozygously deleted for alpha-synuclein by targeted disruption. Alpha-synuclein -/- mice were viable and fertile; they exhibited intact brain architecture and possessed a normal complement of dopaminergic cell bodies, fibers, and synapses. Nigrostriatal terminals of alpha-synuclein -/- mice displayed a standard pattern of dopamine discharge and reuptake in response to simple electrical stimulation. However, they exhibited an increased release with paired stimuli that could be mimicked by elevated calcium. Concurrent with the altered dopamine release, alpha-synuclein -/- mice displayed a reduction in striatal dopamine and an attenuation of dopamine-dependent locomotor response to amphetamine. These findings supported the hypothesis that alpha-synuclein is an essential presynaptic, activity-dependent negative regulator of dopamine neurotransmission.
Masliah et al. (2000) developed transgenic mice that expressed wildtype alpha-synuclein under the control of the promoter of the platelet-derived growth factor-beta gene (190040), which is expressed in all neurons. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. Masliah et al. (2000) concluded that accumulation of wildtype alpha-synuclein may play a causal role in Parkinson disease and related conditions.
Feany and Bender (2000) produced transgenic fly lines that produced normal human alpha-synuclein and separate lines with each of the 2 mutant proteins linked to familial Parkinson disease, A30P (163890.0002) and A53T (163890.0001) alpha-synuclein. Pan-neural expression of human alpha-synuclein resulted in adult-onset loss of dopaminergic neurons, filamentous intraneuronal inclusions containing alpha-synuclein reminiscent of Lewy bodies, and locomotor dysfunction. Drosophila expressing the A30P alpha-synuclein lost their climbing ability earlier than flies expressing wildtype or A53T alpha-synuclein. However, all transgenic flies showed premature loss of climbing ability. In addition to degenerative changes in the brain, retinal degeneration also occurred when alpha-synuclein was expressed specifically in the eye. Expression of wildtype or mutant alpha-synuclein during development of the eye produced no effect. However, continued expression of alpha-synuclein in the adult produced retinal degeneration that was detectable by 10 days and marked at 30 days in transgenic flies expressing wildtype, A30P, or A53T alpha-synuclein.
Auluck et al. (2002) investigated whether HSP70 (140550) could mitigate dopaminergic neuron loss induced by alpha-synuclein in flies with mutated alpha-synuclein. They used a transgenic line encoding human HSP70 to coexpress HSP70 with alpha-synuclein. Upon coexpression of HSP70, Auluck et al. (2002) found complete maintenance of normal numbers of dopaminergic neurons in aged flies. Although alpha-synuclein expression in the absence of HSP70 resulted in a 50% loss of these neurons in dorsomedial clusters by 20 days, in the presence of added HSP70, the same number of dopaminergic neurons were present at 20 days as were present at 1 day. Protection was specific to HSP70.
Some patients have clinical and pathologic features of Alzheimer disease and Parkinson disease, raising the possibility of overlapping pathogenetic pathways. Masliah et al. (2001) generated transgenic mice with neuronal expression of human beta-amyloid peptides, alpha-synuclein, or both. The functional and morphologic alterations in doubly transgenic mice resembled the Lewy body variant of Alzheimer disease (127750). These mice had severe deficits in learning and memory, developed motor deficits earlier than the alpha-synuclein singly transgenic mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein singly transgenic mice. Ultrastructurally, some of these inclusions were fibrillar in doubly transgenic mice, whereas all inclusions were amorphous in alpha-synuclein singly transgenic mice. Beta-amyloid peptides promoted aggregation of alpha-synuclein in a cell-free system and intraneuronal accumulation of alpha-synuclein in cell culture. Beta-amyloid peptides may contribute to the development of Lewy body diseases by promoting the aggregation of alpha-synuclein and exacerbating alpha-synuclein-dependent neuronal pathologic changes. Therefore, treatments that block the production of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.
To better understand the pathogenic relationship between alterations in the biology of alpha-synuclein and PD-associated neurodegeneration, Lee et al. (2002) generated multiple lines of transgenic mice expressing the human SNCA mutations A30P or A53T. The mice expressing the A53T human alpha-synuclein, but not wildtype or the A30P variant, developed adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibited neuronal abnormalities (in perikarya and neurites) including pathologic accumulations of alpha-synuclein and ubiquitin. Alpha-synuclein-dependent neurodegeneration was associated with abnormal accumulation of detergent-insoluble alpha-synuclein.
Ihara et al. (2007) found that deletion of Sept4 (603696) in transgenic mice expressing human alpha-synuclein with the PD-associated A53T mutation exacerbated PD-like symptoms, including elevated amyloid deposits containing pathologically phosphorylated alpha-synuclein and more severe loss of motor neurons and astrocyte gliosis. In vitro studies showed that Sept4 interacted directly with alpha-synuclein, suppressed self-aggregation of mutant alpha-synuclein, and partially interfered with pathologic phosphorylation of mutant alpha-synuclein. Ihara et al. (2007) concluded that SEPT4 may prevent alpha-synuclein self-aggregation or shield alpha-synuclein from serine phosphorylation in PD.
MPTP, a neurotoxin that inhibits mitochondrial complex I (see 252010), is a prototype for an environmental cause of PD because it produces a pattern of neurodegeneration of dopamine neurons that closely resembles the neuropathology of PD. Dauer et al. (2002) showed that alpha-synuclein-null mice displayed striking resistance to MPTP-induced degeneration of dopamine neurons and dopamine release; this resistance appeared to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance was not due to abnormalities of the dopamine transporter, which appeared to function normally in the null mice. The results suggested that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and demonstrated that normal alpha-synuclein function may be important to dopamine neuron viability.
Junn et al. (2003) demonstrated that tissue transglutaminase (190196) catalyzes the formation of alpha-synuclein aggregates in vitro and also in cellular models. Furthermore, they showed the presence of epsilon(gamma-glutamyl)-lysine bonds, which is indicative of transglutaminase activity, in Parkinson disease with Lewy bodies (605543) and in dementia with Lewy bodies (127750). The findings suggested that this enzyme is involved in the formation of Lewy bodies by crosslinking alpha-synuclein and possibly in the pathogenesis of alpha-synucleinopathies.
To identify genes influencing alcohol consumption, Liang et al. (2003) used QTL and gene expression analyses as complementary methods in a study of inbred alcohol-preferring (iP) and alcohol-nonpreferring (iNP) Wistar rat strains, showing highly discordant alcohol consumption scores. A genome screen identified QTLs on chromosomes 3, 4, and 8. The chromosome 4 QTL produced a lod score of 9.2 that accounted for 10% of the phenotypic and approximately 30% of the genetic variation in alcohol consumption. The gene expression analysis identified differential expression of genes and 3-prime ESTs. Of the genes that were differentially expressed in iP and iNP rats, SNCA was prioritized for further investigation because it was located in a region of mouse chromosome 6 syntenic to the rat chromosome 4 QTL, and it was shown to modulate dopamine transmission, which was thought to be involved with neurodegenerative and neuropsychiatric disorders such as alcoholism (103780). Liang et al. (2003) found that alpha-synuclein was expressed in the hippocampus at more than 2-fold higher levels in the iP than in the iNP rats. In situ hybridization demonstrated that protein levels in the hippocampus were also higher in iP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified 2 SNPs in the 3-prime UTR of the SNCA cDNA. One of the SNPs was used to map the gene, by using recombination-based methods, to a region within the chromosome 4 QTL. A nucleotide exchange in the iNP 3-prime UTR reduced expression of the luciferase reporter gene in cultured neuroblastoma cells. These results suggested that differential expression of the SNCA gene may contribute to alcohol preference in the iP rats.
Transgenic Drosophila expressing human SNCA carrying the ala30-to-pro (A30P; 163890.0002) mutation faithfully replicate essential features of human Parkinson disease, including age-dependent loss of dopaminergic neurons, Lewy body-like inclusions, and locomotor impairment. Scherzer et al. (2003) characterized expression of the entire Drosophila genome at presymptomatic, early, and advanced disease stages. Fifty-one signature transcripts were tightly associated with A30P SNCA expression. At the presymptomatic stage, expression changes revealed specific pathology. In age-matched transgenic Drosophila carrying an arg406-to-trp mutation in tau (157140.0003), the transcription of mutant SNCA-associated genes was normal, suggesting highly distinct pathways of neurodegeneration.
Chen and Feany (2005) found that aged Drosophila expressing wildtype human SNCA developed dopaminergic neuron loss associated with SNCA phosphorylated at ser129. The ser129-to-ala mutation, which is resistant to phosphorylation, suppressed neuronal loss and increased insoluble inclusion body formation. In contrast, ser129 to asp, which mimics phosphorylation, resulted in increased neuronal SNCA toxicity. Chen and Feany (2005) suggested that sequestration of alpha-synuclein into insoluble inclusion bodies may protect cells from neurotoxicity. and that ser129 is essential for the toxicity of SNCA in dopaminergic neurons.
Mutations in the human ATP13A2 gene (610513) result in PARK9 (KRS; 606693). Gitler et al. (2009) showed that the yeast homolog of human ATP13A2, termed Ypk9, could suppress overexpression-induced Snca toxicity both in yeast and in cultured rat dopaminergic neurons by decreasing intracellular Snca inclusions. Ypk9 knockdown in C. elegans enhanced misfolding of Snca. In addition, Ypk9 was found to help protect cells from manganese toxicity. These findings suggested a functional connection between Snca and the PARK9 susceptibility locus, as well as with manganese exposure as a possible environmental risk factor for PD.
Using recombinant adenovirus-associated vector (rAAV2/6)-mediated expression of alpha-synuclein, Azeredo da Silveira et al. (2009) developed a rat model of PD in which there was a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. Serine-129 has been shown to be the major phosphorylation site on alpha-synuclein in PD patients (see Fujiwara et al., 2002 and Anderson et al., 2006). Azeredo da Silveira et al. (2009) demonstrated that a mutation preventing phosphorylation (ser129 to ala; S129A) significantly increased alpha-synuclein toxicity and led to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments, and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (ser129 to asp; S129D) did not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates were formed, and signals of apoptosis were also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. Azeredo da Silveira et al. (2009) suggested that phosphorylation does not play an active role in the accumulation of cytotoxic preinclusion aggregates, and that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration.
Cronin et al. (2009) reported the effects of 3 distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA mRNA and protein concentrations in murine brain but no decrease was observed in blood lysates from the same mice. Cronin et al. (2009) concluded that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system, and suggested that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.
Lin et al. (2009) found that overexpression of Lrrk2 (609007), either wildtype or mutant, in transgenic mice carrying an A53T Snca mutation (163890.0001) accelerated the PD-related neuropathologic abnormalities by promoting aggregation and accumulation of cytotoxic Snca-containing protein inclusions in cell bodies of striatal neurons. However, the 2 proteins did not appear to interact directly. Degenerating neurons showed fragmentation of the Golgi apparatus, which correlated with the accumulation of Snca. Immunostaining studies showed evidence of impaired microtubule assembly within the cells as well as impairment of the ubiquitin-proteasome system. Mitochondrial function was also impaired. Inhibition of Lrrk2 in these mice suppressed these abnormalities and delayed the progression of neuropathology in A53T mutant mice. The findings suggested that Lrrk2 may regulate mutant Snca-mediated neuropathology by modulating the intracellular trafficking and microtubule-based axonal transport of Snca.
Ramsey et al. (2010) noted that several in vitro studies had suggested that DJ1 (602533) could inhibit the formation and protect against the effects of SNCA aggregation. They crossbred transgenic mice (M83) expressing the human pathogenic SNCA A53T mutation (163890.0001) on a DJ1-null background (M83-DJ-null mice) to determine the effects of the lack of DJ1 in these mice. M83 and M83-DJ-null mice displayed a similar onset of disease and pathologic changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJ-null mice. The authors suggested that DJ1 may not function to modulate SNCA directly and does not appear to play a role in protecting against the deleterious effects of A53T in vivo. Ramsey et al. (2010) speculated that SNCA and DJ1 mutations may lead to Parkinson disease via independent mechanisms.
Kuo et al. (2010) developed transgenic mice expressing mutant alpha-synuclein, either A53T (163890.0001) or A30P (163890.0002), from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines showed abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also had abnormal motor behavior, but neither line demonstrated cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions, or neurodegeneration. These animals recapitulated the early gastrointestinal abnormalities seen in human Parkinson disease.
Using a mouse prion protein promoter, Smith et al. (2010) generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T alpha-synuclein double-transgenic mice survived longer than A53T alpha-synuclein single-transgenic mice. There were attenuated A53T alpha-synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 (CASP3; 600636) activation, increased beclin-1 (BECN1; 604378) and LC3 II (see 601242) expression, and promoted formation of aggresome-like structures, suggesting that synphilin-1 may alter multiple cellular pathways to protect against neuronal degeneration. The authors concluded that synphilin-1 can diminish the severity of alpha-synucleinopathy and may play a neuroprotective role against A53T alpha-synuclein toxicity in vivo.
Using transgenic mice, Taguchi et al. (2020) found that the expression pattern of human SNCA harboring the A53T mutation, 2 SNPs associated with PD in a genomewide association study (rs11931074 and rs3857059), and a Rep1 polymorphism closely resembled that of endogenous mouse Snca. However, the amount of truncated, triton-insoluble, and proteinase K-resistant SNCA was increased in transgenic mice. Transgenic mice also displayed degeneration of dopaminergic neurons in substantia nigra pars compacta, with increased oligomeric species of SNCA. Further analysis revealed rapid eye movement sleep behavior disorder-like behavior and hyposmia in transgenic mice.
Argyrofthalmidou et al. (2021) crossed Nurr1 (NR4A2; 601828) +/- and transgenic mice expressing the human SNCA A53T mutation (163890.0001) implicated in Parkinson disease (PD) to obtain various genotypes. Nurr1 -/- genotypes were born at the expected mendelian ratio but died after birth. Nurr1 -/+ mice with homozygosity for alpha-synuclein-A53T (ASYN(d)/Nurr1 -/+), which the authors termed 2-hit mice, displayed reduced total spontaneous locomotor activity at 6 months of age compared to controls. However, as the animals aged, the decline was less pronounced and was not statistically different from that of controls by 9 months of age. Decline in exploratory activity was attributed to levels of Nurr1 expression. Aging 2-hit mice displayed a phenotype consistent with dopaminergic dysfunction and similar to human PD, with reduced body weight, kyphosis, severe rigid paralysis, movement impairment, and cachexia, and died prematurely. 2-hit mice had substantia nigra (SN) neuron degeneration, extensive neuroinflammation, and enhanced alpha-synuclein aggregation. Movement impairment was L-DOPA responsive. ASYN(d)/Nurr1 +/+ mice or Nurr1 +/- mice with transgenic alpha-synuclein heterozygosity (ASYN(s)/Nurr1 +/-) did not develop PD-like phenotype or pathology. Nurr1 expression was found to be progressively downregulated in aging transgenic mice with heterozygous or homozygous alpha-synuclein overexpression, and it was even further reduced in aging 2-hit mice. These results demonstrated that PD-related pathophysiology caused by SNCA mutation was mediated at least in part by Nurr1 downregulation, and that the combination of mutant alpha-synuclein overexpression and Nurr1 downregulation was essential and sufficient to cause PD-related abnormalities.
In affected members of a large Italian family with an early-onset form of autosomal dominant Parkinson disease (PARK1; 168601), and in 3 other unrelated Greek families, Polymeropoulos et al. (1997) demonstrated a heterozygous ala53-to-thr (A53T) mutation in the SNCA gene, resulting from a 209G-A transition. The mutation generates a novel Tsp45I restriction site in the gene.
Vaughan et al. (1998) studied all 7 exons of the SNCA gene in 30 European and American Caucasian kindreds affected with autosomal dominant PD and found no instance of the A53T mutation or any other mutation. In a large screening of patients with PD, Farrer et al. (1998) also found no genetic variation in the SNCA gene. Ho and Kung (1998) failed to find the A53T missense mutation in 118 Chinese sporadic PD patients from Hong Kong or 124 control subjects. They also did not find the mutation in 9 sporadic PD cases from Birmingham, U.K., or 10 control subjects from the same area.
Athanassiadou et al. (1999) studied 19 unrelated families, each of which contained at least 2 first- or second-degree relatives affected with PD. A heterozygous A53T mutation was detected in 10 patients belonging to 7 autosomal dominant families, but was not found in any member of the remaining 12 families. In patients carrying the mutation, the mean age at onset of the disorder was 47 +/- 11 years, which was considered to be early onset. In 1 family, a patient with a much later age at onset of the disease, 76 years, did not carry the A53T mutation.
In the southern Italian kindred originally reported by Polymeropoulos et al. (1997) and the 7 Greek families that carried the A53T mutation, Athanassiadou et al. (1999) studied 10 polymorphic markers. A shared haplotype was considered consistent with a founder chromosome. Clinically, the A53T cases, in addition to early age at onset, showed prominent bradykinesia and muscular rigidity but rarely had tremor. All 7 Greek families with PD studied by Athanassiadou et al. (1999) originated from 3 villages of the northern Peloponnese in Greece; 6 of the families were from 2 villages only 17 km apart. The Italian kindred came from southern Italy, a region geographically and historically linked to Greece.
Spira et al. (2001) reported a family of Greek origin with 5 of 9 sibs affected with PD, 3 of whom were examined in detail and were found to carry the A53T mutation. The 3 sibs presented in their forties with progressive bradykinesia and rigidity, which was initially dopa-responsive, and cognitive decline. Additional features included central hypoventilation, postural hypotension, bladder incontinence, and myoclonus. Neuropathologic examination showed depigmentation of the substantia nigra, severe cell loss and gliosis in the brainstem, and multiple alpha-synuclein-immunopositive Lewy neurites. Cortical neuritic changes associated with tissue vacuolization were present, mostly in the medial temporal regions.
Ki et al. (2007) identified a heterozygous A53T mutation in a Korean man with early-onset PD at age 37 years. A clinically unaffected 45-year-old brother also carried the mutation. The brothers' mother had onset of PD at age 63 years and died at age 67; mutation analysis was not performed. Haplotype analysis showed that this mutation occurred on a different haplotype from that described in Greek and Italian individuals.
Choi et al. (2008) identified the A53T mutation in 1 of 72 unrelated Korean patients with onset of Parkinson disease before age 50. Family history was consistent with autosomal dominant inheritance.
Puschmann et al. (2009) reported 2 affected members of a Swedish family with the A53T mutation. Haplotype analysis indicated a different haplotype than the Greek founder haplotype, suggesting a de novo event in the Swedish family. The proband had insidious onset of decreased range of motion, stiffness, and hypokinesia between ages 39 and 41 years. About 6 months later, she developed word-finding difficulty and monotone speech. The disorder was progressive, and she developed dementia and severe motor disturbances, including myoclonus, by age 47. Her father developed motor signs of the disorder at age 32, with speech difficulties at age 33. At age 38, he was moved to a nursing home, and at 40, he was aphonic with dementia and an inability to walk or feed himself independently. Both patients had normal brain MRI and increased CSF protein levels, SPECT scan of the daughter showed decreased blood flow in the language region. Puschmann et al. (2009) emphasized the early onset, rapid progression, and presence of dementia in this family, and suggested that an underlying cortical encephalopathy contributed to the disease course.
Voutsinas et al. (2010) performed studies on lymphoblastoid cells derived from a female PD patient who was heterozygous for the A53T mutation. RT-PCR showed that the mutant A53T protein was not expressed, and there was only monoallelic expression of the normal SNCA allele. Treatment of her cells with a chromatin modifier resulted in reactivation of the silenced mutant allele, indicating that an epigenetic effect, likely via histone modification, was responsible for the silencing. There was no evidence for changes in methylation. Compared to normal individuals, the patient had an average of a 2-fold increase in total SNCA mRNA. The findings indicated an overall imbalance of allelic expression of the SNCA gene, with the normal allele expressed at a higher level than normal. The report was consistent with the observation that overexpression of the wildtype SNCA gene (see, e.g., 163890.0005) can also cause Parkinson disease.
To investigate further the role of alpha-synuclein in familial Parkinson disease (PARK1; 168601), Kruger et al. (1998) undertook mutation analysis of all 5 translated SNCA exons in 192 sporadic cases and in 7 unrelated patients with a family history for Parkinson disease. None of the patients was found to carry the A53T mutation (163890.0001). One patient was found to carry a heterozygous 88G-C transversion in exon 3, resulting in an ala30-to-pro (A30P) substitution. The index patient developed signs of progressive parkinsonism at 52 years of age. His mother presented with symptoms at age 56 and died from the disease at age 60. A younger sib, aged 55, reported impaired motor function in the right arm and neurologic findings of Parkinson disease. The 33-year-old child of the index patient and a 50-year-old sib were carriers of the mutation. Both exhibited subtle neurologic disturbances. The A30P substitution was not found in 1,140 control chromosomes. Kruger et al. (1998) concluded that mutations in the SNCA gene participate in the pathogenesis of some rare cases of Parkinson disease.
Kruger et al. (2001) characterized the disease phenotype caused by the A30P mutation and found that it is similar to that of typical PD, including cardinal features of PD and positive and sustained response to L-DOPA therapy. Two affected members of 1 family showed striatal dopaminergic abnormalities on PET scan similar to those in sporadic PD. Cognitive impairment was noted as an early and frequent finding.
Seidel et al. (2010) reported neuropathologic findings of a patient with PD due to the A30P mutation. He had onset at age 54 years, had L-DOPA-related complications, and died in a mute, bedridden state at age 69. Postmortem examination showed depigmentation and neuronal loss in the substantia nigra and neuronal loss in the locus ceruleus and dorsal motor vagal nucleus. There were widespread SNCA-positive Lewy bodies, Lewy neurites, and glial aggregates in the cerebral cortex and many other regions of the brain, including the hippocampus, hypothalamus, brainstem, and cerebellum. Biochemical analysis showed a significant load of insoluble SNCA.
Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring the A53T alpha-synuclein mutation. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen (Tardiff et al., 2013), and NEDD4 (602278), the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons.
By quantitative PCR amplification of SNCA exons in an individual with parkinsonism (PARK4; 605543) from a family reported by Waters and Miller (1994), Singleton et al. (2003) found evidence consistent with whole gene triplication. Analysis of other family members showed that the SNCA triplication segregated with parkinsonism, but not with postural tremor. The authors found that the telomeric end of the triplication occurs within the model gene KIAA1680 (GenBank AB051467), and the centromeric end occurs between exon 23 of the cyclin E-binding protein gene (608242) and exon 7 of hypothetical protein DKFZp761G058 (GenBank AK054678). The triplicated region contains an estimated 17 genes, including SNCA. Carriers of the triplication are predicted to have 4 fully functional copies of SNCA, with doubling of the effective load of the estimated 17 genes. The authors suggested that increased dosage of SNCA is the cause of PD in this family, and noted that the disease process may resemble the etiology of Alzheimer disease in Down syndrome (190685) with overexpression of the APP gene due to chromosome 21 trisomy.
In affected patients with the SNCA triplication, Miller et al. (2004) found an approximately 2-fold increase in SNCA protein in blood, a 2-fold increase of SNCA mRNA in brain tissue, and increased levels of heavily aggregated SNCA protein in brain tissue. The authors concluded that all 4 alleles were expressed and that increased expression of the SNCA protein promoted aggregation and deposition in brain tissue, thus contributing to disease.
Farrer et al. (2004) identified a family of Swedish American descent with autosomal dominant early-onset parkinsonism and dementia due to a triplication of the SNCA gene. The phenotype included rapidly progressive parkinsonism, dysautonomia, and dementia. Fuchs et al. (2007) determined that the family reported by Farrer et al. (2004) was a branch of a large family originally reported by Mjones (1949). Fuchs et al. (2007) identified a Swedish branch of the family who had parkinsonism and dementia due to a duplication of the SNCA gene (163890.0005). Genotypes within and flanking the duplicated region in the Swedish family were identical to genotypes in the Swedish-American family reported by Farrer et al. (2004), suggesting a common founder. Hybridization signals indicated a tandem multiplication of the same genomic interval in the 2 families, a duplication and triplication, respectively. Sequence analysis indicated that the multiplications were mediated by centromeric and telomeric long interspersed nuclear element (LINE L1) motifs.
In affected members of a Spanish family with autosomal dominant Lewy body dementia (127750) and parkinsonism, Zarranz et al. (2004) identified a 188G-A transition in the SNCA gene, resulting in a glu46-to-lys (E46K) substitution in the amino-terminal region of the protein. The mutation showed complete segregation with the disease phenotype and was absent in 276 Spanish healthy and disease controls.
Choi et al. (2004) found that the E46K SNCA mutation resulted in a significant increase in alpha-synuclein binding to negatively charged phospholipid liposomes compared to the wildtype, A53T (163890.0001), and A30P (163890.0002) mutant proteins. The A30P mutant had decreased binding, and the A53T mutant had binding similar to wildtype. The mutated E46K protein had an increased rate and amount of filament assembly compared to wildtype and the A30P mutant. The E46K mutant filaments had a pronounced twisted appearance with width varying between about 5 and 14 nm and a crossover spacing of 43 nm, yielding arrays with a meshwork appearance. The A53T mutant had an increased rate and amount of filament assembly, yielding a twisted appearance with a width between 5 and 14 nm and a crossover spacing of approximately 100 nm. The A30P mutant showed a slower rate of filament assembly compared to wildtype, but the total number of filaments formed was greater than wildtype. The appearance of the A30P filaments was similar to wildtype, characterized by a 6 to 9-nm width. The findings suggested a mechanism for the pathogenicity of E46K.
Greenbaum et al. (2005) also showed that the E46K mutation resulted in increased amyloid fibril assembly compared to the wildtype protein, but the effect was not as strong as that of the A53T mutation. Synthetic E46A, E83K, and E83A mutations had the same effect, suggesting that N-terminal glu residues modulate filament formation.
In affected members of 3 unrelated families, 2 French and 1 Italian, with autosomal dominant Parkinson disease (PARK1; 168601), Ibanez et al. (2004) and Chartier-Harlin et al. (2004) identified heterozygosity for whole-gene duplication of the SNCA gene. In all patients, the phenotype was typical for idiopathic PD, with a slightly earlier age at onset (39 to 65 years). Affected individuals had bradykinesia, rigidity, resting tremor, and a favorable response to levodopa treatment. In contrast to the family with SNCA triplication (see 163890.0003 and Singleton et al., 2003), patients with the SNCA duplication did not have signs of dementia or other atypical features. Ibanez et al. (2004) and Chartier-Harlin et al. (2004) concluded that there was a clear gene dosage effect that correlated with the severity of the disease and suggested that genetic variability within the SNCA promoter may also play a role in the susceptibility to PD.
Nishioka et al. (2006) identified heterozygosity for duplication of the SNCA gene in 2 of 113 Japanese probands with autosomal dominant PD. The length of the duplication in 1 proband was approximately 220 kb, spanning all of SNCA and exons 1-6 of MMRN1 (601456); in the second proband, the duplication was approximately 394 kb, spanning all of SNCA and all of MMRN1. In the first family, 2 patients with the duplication had typical PD, whereas 4 duplication carriers over the age of 43 years were unaffected, yielding a penetrance of 33%. In the second family, 1 affected and 2 asymptomatic members had the duplication. The affected patient from the second family developed dementia 14 years after diagnosis of PD, and neuropathologic examination (Obi et al., 2008) was found to be consistent with dementia with Lewy bodies (127750).
Fuchs et al. (2007) reported a Swedish kindred with Parkinson disease due to a duplication of the SNCA and MMRN1 genes. Clinical features included autonomic dysfunction and rapidly progressive motor symptoms. Myoclonus and dementia occurred late in the disease. This family was determined to be a branch of a large family originally reported by Mjones (1949). A Swedish American branch of that family was found by Farrer et al. (2004) to have a triplication of the SNCA gene (163890.0003). Fuchs et al. (2007) found that genotypes within and flanking the duplicated region in the Swedish family were identical to genotypes in the Swedish American family reported by Farrer et al. (2004), suggesting a common founder. Hybridization signals indicated a tandem multiplication of the same genomic interval in the 2 families, a duplication and triplication, respectively. Sequence analysis indicated that the multiplications were mediated by centromeric and telomeric long interspersed nuclear element (LINE L1) motifs.
Ahn et al. (2008) identified an SNCA gene duplication in 3 of 906 Korean patients with Parkinson disease. Only 1 patient had a family history of the disorder; he presented with early onset at age 40 and rapidly progressive disease complicated by dementia. Two of his brothers with the duplication were asymptomatic at 51 and 47 years, respectively, indicating reduced penetrance.
Brueggemann et al. (2008) and Troiano et al. (2008) independently identified duplications of the SNCA gene in 2 patients with sporadic early-onset PD, at ages 36 and 35 years, respectively. The mutation was confirmed to be de novo in the case of Brueggemann et al. (2008). Neither patient had cognitive impairment. The prevalence of the SNCA duplication in sporadic PD was reported to be 0.25% and 1%, respectively.
Uchiyama et al. (2008) reported a Japanese mother and son with duplication of the SNCA gene associated with variable features of parkinsonism and dementia. The son had prominent parkinsonism in his late forties, followed by fluctuating cognitive decline, visual hallucinations, and deficits in verbal fluency a few years later. The mother presented later at age 72 with memory disturbances and fluctuating cognitive deficits. She then developed mild parkinsonism and visual hallucinations. PET studies showed that both patients had diffuse hypometabolism in the brain that extended to the occipital visual cortex in the mother. Uchiyama et al. (2008) noted that the diagnoses in the son and mother were compatible with PD dementia and Lewy body dementia, respectively.
In 4 members of a French family with autosomal dominant PD (PARK1; 168601) and spasticity, Lesage et al. (2013) identified a heterozygous c.152G-A transition in the SNCA gene, resulting in a gly51-to-asp (G51D) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Sequencing Project databases, or in 236 control individuals. In vitro cellular expression studies showed that the mutant G51D protein assembled into high molecular weight fibrils in a concentration-dependent manner, similar to wildtype and to A53T (163890.0001). Sedimentation velocity experiments showed that the proportion of oligomeric G51D SNCA in solution was significantly lower than that of wildtype or A53T. Mutant G51D and wildtype SNCA coassembled, such that fibrils of each protein seeded soluble oligomer assembly of the other. Fibrillar G51D decreased cell survival by enhancing caspase-3 (CASP3; 600636) activity. The patients had a unique disorder comprising rapidly progressive Parkinson disease, spasticity, and psychiatric features. Three affected individuals had onset at age 31 to 35 years, whereas the fourth had onset at age 60. The disorder was rapidly progressive: all became bedridden within 5 to 7 years, and 3 patients died within 5 to 7 years of onset. Neuropathologic examination of 1 patient showed neuronal loss in the substantia nigra and striatum, as well as astrogliosis. There was also neuronal loss in the motor cortex, the anterior horn of the spinal cord, and the corticospinal tracts. Lewy bodies and dystrophic Lewy neurites were present mostly in the brainstem. There were fine, diffuse, neuronal cytoplasmic inclusions in all superficial cortical layers. Lesage et al. (2013) suggested that the structural and aggregative properties of the mutant protein did not fully account for the pathology, and postulated that undefined abnormal protein interactions may also have contributed.
In a Caucasian English woman with PARK1 (168601), Proukakis et al. (2013) identified a heterozygous c.150T-G transversion in exon 3 of the SNCA gene, resulting in a his50-to-gln (H50Q) substitution at a conserved residue in a copper-binding region. The mutation, which was found by direct sequencing of the SNCA gene, was not present in the 1000 Genomes Project database or in 450 control DNA samples. Electron paramagnetic resonance studies indicated that the mutant residue was able to bind copper, but in contrast to wildtype, there was no participation in metal coordination from other portions of the protein. The patient developed PD at age 71, became forgetful at 80, and died at 83. Autopsy confirmed PD, with loss of pigmented cells in the substantia nigra and presence of Lewy bodies; plaques and neurofibrillary tangles were also noted in the cortex and hippocampus. There was no family history of a similar disorder.
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