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Lo DC, Hughes RE, editors. Neurobiology of Huntington's Disease: Applications to Drug Discovery. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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Neurobiology of Huntington's Disease: Applications to Drug Discovery.

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Chapter 3Protein Interactions and Target Discovery in Huntington’s Disease

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INTRODUCTION

Huntington’s disease (HD) is a devastating neurological disorder for which we currently have no effective treatments. Although patients are typically treated with drugs that can modify symptoms, none of these current drug regimens are thought to modify the onset, progress, or ultimate fatality of HD. A major step forward in terms of understanding the mechanism underlying HD and thus toward developing rational approaches to drug development occurred in 1993 with the cloning of the HD gene (Willard, 1993). From a drug development perspective, one great outcome of this advancement was to create the ability to express the mutant HD gene in cell-based and transgenic models that can experimentally recapitulate aspects of HD pathology (see Chapters 5, 6, and 7, this volume). Such assays are invaluable tools for characterizing pathogenic mechanisms and discovering targets and small molecule modifiers of toxicity mediated by mutant Htt expression. The identification of the protein also allows us to determine its interacting partners and thereby place the pathogenesis of the disease in a proteomic context. However, despite early enthusiasm suggesting that the discovery of the precise genetic cause of HD could provide a fast track to an effective treatment, disease-modifying small molecule interventions for HD remain to be fully developed.

Target discovery and target validation are key early steps in the drug discovery process (see Chapter 4, this volume). There are a number of approaches to target discovery that include nomination and testing of candidate targets based on consideration of biological and molecular features of specific diseases. Candidate targets can also be inferred from genetic modifier screens in model organisms such as Caenorhabditis elegans and Drosophila (see Chapter 6, this volume). More recently, high-throughput RNA interference (RNAi) screening in cell-based models of disease has provided an opportunity to use unbiased genome-wide screens to identify potential targets capable of modifying in vitro models of disease phenotypes (Cronin et al., 2009; Krishnan et al., 2008; Luo et al., 2009). Candidate genes identified through RNAi-mediated phenotypes can be further validated in higher content models, such as crossing transgenic HD mice with a strain that bears a genetic modification of a candidate target. Another powerful method for target identification is the use of protein interaction studies. This chapter will focus on the role of protein interactions in HD and specifically on how knowledge of protein interaction networks can inform target discovery and validation processes for HD drug development.

PROTEIN INTERACTIONS IMPLICATE MECHANISMS AND TARGET PATHWAYS IN HD

The precise pathogenic mechanisms underlying HD remain relatively unclear. An interesting phenomenon contributing to this uncertainty may be the great number of pathways that have been reported to be dysfunctional in cell- and organism-based models of this disease. Pathways that have been implicated as impaired in HD include transcriptional regulation, vesicle transport, mitochondrial energy production, synaptic function, and protein homeostasis (Landles and Bates, 2004). Despite the fact that there have been a number of cellular dysfunctions associated with expanded Htt expression, components of these dysfunctional pathways should not be assumed to be de facto targets for HD. Candidate targets are typically defined as gene products whose activities can modify the progress or severity of a disease state.

In many cases of dysfunctional pathways linked to HD, there have been specific protein-interaction partners discovered for huntingtin that either initially implicated a particular pathway, offered corroborative evidence, and/or provided a specific target within a pathway of interest as being mechanistically important. Htt protein interactions and their putative roles in specific pathogenic processes have been reviewed elsewhere (Harjes and Wanker, 2003; Li and Li, 2004).

TECHNOLOGIES FOR DETECTION OF PROTEIN INTERACTIONS AND PROTEIN COMPLEXES

There are a number of established techniques for the discovery and characterization of protein interactions. Currently, the two most commonly used techniques for the high-throughput identification of protein-interacting partners and complexes are yeast two-hybrid (Y2H) screening and tandem affinity purification followed by mass spectrometric analysis. Each of these techniques will be described briefly.

An understanding of protein interactions at the level of individual proteins and in the context of the cellular network is now considered to be a key step toward elucidation of biological functions and processes. Traditionally, the discovery and characterization of protein interactions through classic biochemical methods such as chromatography and chemical sequencing was a slow and laborious process. The invention of Y2H screening technology represented a powerful leap forward in our ability to rapidly and unambiguously identify binary interactions for a given protein at the genome-scale level (Fields and Song, 1989; Miller and Stagljar, 2004). This genetic technology is based on the modular nature of transcription factors that allows for DNA-binding domains and transcriptional activation domains to be noncovalently reassociated through interactions by fusion protein partners. Although initially practiced on a single protein basis, the automation of Y2H allowed this technique to become a major contributor to proteome-scale protein-interaction mapping (Rual et al., 2005; Schwikowski et al., 2000; Stelzl et al., 2005; Uetz et al., 2000). The application of high-throughput Y2H technology to questions relevant to HD research is discussed below.

A complementary biochemical technology for discovery of protein interactions is tandem affinity purification (TAP) of protein complexes followed by protein identification using mass spectrometry (MS) (Collins and Choudhary, 2008; Kaiser et al., 2008). This technology often uses bait proteins of interest fused to TAP tags that allow for high levels of protein complex purity. In contrast to Y2H technology, which provides information about binary interactions, TAP-MS analysis provides information about protein complexes. It is important to note the output of TAP-MS does not provide information about potential pair-wise connectivities between proteins detected as being present in a complex. Like Y2H, TAP-MS has been scaled to a level that can approach genome-wide analysis, at least in model systems such as yeast (Gavin et al., 2002; Ho et al., 2002; Krogan et al., 2006).

LARGE-SCALE INTERACTION NETWORKS AND NEXT-GENERATION DATA MINING

The conventional application of protein-interaction discovery as a “one-off” experiment is gradually giving way to high-throughput methods that allow for parallel screening and complex network generation. To date, two high-throughput protein interaction studies centered on huntingtin protein interactions have been published. In the study of Goehler et al. (2004), a combination of library-based and matrix-based screening was used to generate a huntingtin protein interaction network containing 186 protein interaction pairs. Further analysis and validation of proteins contained in this network revealed that GIT1, a protein interacting directly with huntingtin in the network, could modify huntingtin aggregation in cultured mammalian cells and is colocalized with huntingtin-containing aggregates in the brains of mouse models of HD and in postmortem human HD brain tissue. It is not clear how GIT1, a G proteincoupled receptor kinase-interacting protein involved in cytoskeletal and membrane functions, may modify HD, but the discovery that this protein does associate with huntingtin in HD brain underscores the values of mining large-scale protein interaction networks to identify candidate targets.

Another large-scale interaction network centered on huntingtin was generated using the complementary approaches of Y2H and affinity purification/MS (Kaltenbach et al., 2007; Li and Li, 2004). This study involved exhaustive two-hybrid searches using huntingtin as a bait to screen multiple human cDNA libraries. In parallel, purified amino-terminal huntingtin protein fragments were used to probe soluble protein tissue lysates prepared from mouse brain, mouse muscle, and postmortem human brain samples. Overall, these protein interaction screens identified 104 proteins by Y2H and 130 proteins by TAP. An intriguing feature of this study was the functional validation observed by testing a large number of the interacting proteins for their ability to modify neurodegeneration in a fly model of HD. Drosophila orthologues of genes encoding interacting proteins were tested for their ability to act as modifiers of retinal degeneration in transgenic flies expressing mutant huntingtin. Of the 60 genes tested, 80% were able to enhance and/or suppress the toxic effects of mutant huntingtin through either overexpression or a partial loss of function. Modifier genes validated in this manner encoded proteins involved in functions such as transcription, signal transduction, and synaptic vesicle fusion. Proteins with functions in synaptic vesicle fusion and neurotransmission (e.g., STX1A, SNAP, and CACNA2D1) were further validated as having a role in mutant huntingtin toxicity in follow-up studies in HD transgenic Drosophila (Romero et al., 2008).

TRANSCRIPTION PROTEIN INTERACTIONS WITH HUNTINGTIN

In this chapter, we will focus on one area of biology that has been the subject of a significant amount of investigation in HD research: transcriptional dysregulation (Butler and Bates, 2006; Cha, 2000, 2007; Hughes, 2002; Sugars and Rubinsztein, 2003). Protein interactions likely play an important role in this facet of the disease as a number of transcription factors contain polyglutamine tracts, and the propensity for these sequences to self-assemble suggests a mechanism by which mutant Htt influences transcription. Furthermore, polyglutamine tracts and polyproline tracts, both of which Htt possesses, can function as transcription-activating domains when fused to a DNA-binding domain (Gerber et al., 1994). Beyond interactions based on polyglutamine tract annealing, Htt also interacts with transcriptional machinery constituents that contain no polyglutamine stretch, or, as in the case of CREB-binding protein (CBP), interacts even after the polyglutamine stretch is removed from the protein (Steffan et al., 2001).

From a therapeutic standpoint, transcription factors that interact with Htt present a class of targets with two opposing intervention strategies. First, in the case where an interaction is seen with normal Htt, but not with mutant Htt, the interaction may be important for cell survival, and stabilizing/enhancing the interaction may be therapeutic. In the alternative situation, wherein mutant Htt interacts with a protein but wild-type Htt does not, inhibition of the interaction, or even levels of the protein itself, is the objective of intervention. This latter circumstance is the more expected case from a theoretical perspective; i.e., the gain of an inappropriate interaction confers the detrimental consequences of the disease protein. However, prominent examples indicate the contribution of the loss of at least some normal interactions is also important in disease etiology (Zuccato et al., 2003).

A number of the transcriptional proteins found to interact with Htt also interact with at least one other Htt-interacting transcription protein (Figure 3.1). Intriguingly, 32 of the transcription-related Htt-interacting proteins form an interconnected group with each other. This suggests that Htt could potentially influence a number of the proteins via its direct interaction with just one of them. On the one hand, wild-type Htt may have a prosurvival role that depends on an interaction with one or more of these proteins. Such an interaction may be reduced or lost with the mutant protein, which additionally interacts inappropriately with other transcription factor proteins, with cytotoxic results.

FIGURE 3.1. The interactions among transcriptionrelated proteins that interact with Htt.

FIGURE 3.1

The interactions among transcriptionrelated proteins that interact with Htt. As discussed in the text, evidence suggests the interaction of Htt with some partners is likely to be beneficial to the cell (green), whereas other interactions are most likely (more...)

The transcription-related protein interactions with Htt will be summarized in this section (Table 3.1). Where there is sufficient evidence to do so, a description of whether the interaction appears beneficial or detrimental is presented. For several prominent examples, approaches that may develop a given interaction into an effective therapeutic target will be discussed. We will focus primarily on directed therapeutic strategies, as the screening for small molecules that remedy transcriptional dysregulation in HD has been explored elsewhere (Kazantsev and Hersch, 2007; Rigamonti et al., 2007), although such strategies have potential applicability to all the interactions discussed.

TABLE 3.1. Transcription-Related Proteins That Interact with Huntingtin.

TABLE 3.1

Transcription-Related Proteins That Interact with Huntingtin.

POTENTIAL PROSURVIVAL PROTEIN INTERACTIONS WITH NORMAL HUNTINGTIN

Of 58 transcription-related proteins (Table 3.1) reported to interact with Htt in the literature, evidence for 14 proteins suggests that the mutant form does not interact to the same extent as the wild type form. If these then represent “normal” interactions, they may contribute to pathology in that they become reduced in abundance or possibly converted to harmful interactions when Htt within the cell harbors an expanded polyglutamine tract. Hence, promotion of these interactions may provide a therapeutic benefit. This may come about by permitting mutant Htt to perform the implicated function normally provided by wild-type huntingtin. Alternatively, an interacting partner that functions to modulate stability or post-translational modifications on Htt may not be as effective in the context of the polyglutamine-expanded protein, and facilitation of the interaction may restore a therapeutic degree of function. Strategies for intervention center around increasing the amount or activity of the “normal” interaction partner, with the hope of thereby promoting the interaction.

BAZ1A (hACF1)

Bromodomain adjacent to zinc finger domain 1A (BAZ1A) is a component of an ATP- using chromatin assembly and remodeling factor complex (He et al., 2006) that interacts with nuclear receptor corepressor 1 (N-CoR-1) and is important in repressing transcription within unliganded nuclear hormone receptor complexes (Ewing et al., 2007). BAZ1A was found to interact more strongly with wild-type Htt fragments than with mutant Htt fragments in a Y2H study, suggesting a detrimental effect on the interaction of the expanded polyglutamine tract (Kaltenbach et al., 2007). Hence, the BAZ1A interaction with Htt may be part of the normal function for both proteins. One hypothesis is that in the presence of mutant Htt, reduced interaction allows BAZ1A accumulation in the nucleus, creating excessive repression at unliganded nuclear hormone receptor recognition sites. A potential therapeutic approach would then be administration of the appropriate hormones or vitamins (vitamin D3 response sequences are one established N-CoR/SMRT [silencing mediator for retinoid and thyroid hormone receptors] recruiting element that is influenced by BAZ1A function [Ewing et al., 2007]) to reduce the impact of the nuclear BAZ1A repressive presence. Such an approach first requires confirmation of the changes of BAZ1A target genes/regions in HD, as well as an establishment of a role for BAZ1A in disease dysfunction.

CTBP1

The C-terminal binding protein 1 (CTBP1) is a transcriptional repressor that interacts with multiple components of the cellular repression machinery and provides a bridge between more general repressive factors (e.g., histone deacetylases [HDACs]) and DNA-binding transcriptional repressors. Based on the presence of a motif highly conserved in proteins that interact with CTBP1, Kegel et al. (2002) tested the ability of Htt to interact with this repressor. They found that Htt interacts with CTBP1 and that an expanded polyglutamine tract reduced this interaction. Furthermore, full-length wild-type and mutant Htt both behaved as transcriptional repressors for a luciferase reporter, but N-terminal fragments of Htt were only able to repress transcription if they contained a mutant polyglutamine stretch.

Based on these observations, we anticipate that the interaction of wild-type Htt with CTBP1 represents the appropriate interaction and that the reduced binding with mutant Htt results in transcriptional dysregulation. Because of the ability of only mutant Htt N-terminal fragments to repress transcription in the same experimental context (Kegel et al., 2002), it appears the reduced interaction with CTBP1 may allow inappropriate transcriptional repression through these mutant Htt fragments on their own. Strategies to promote the degradation of mutant Htt fragments would then be of therapeutic benefit. Alternatively, enhancement of nuclear export of mutant Htt fragments would be another way to suppress the defective presence of these molecules in the cell.

There is also evidence that CTBP1 may be a scaffold for sumoylation of substrates in repressor complexes that also contain the small ubiquitin-like modifier (SUMO)- conjugating enzyme UBC9 (Kuppuswamy et al., 2008). In this context, the interaction with Htt would be expected to have detrimental consequences, as it is reported that sumoylation of mutant Htt leads to its stabilization and enhances its transcriptional repressive activity toward the multidrug resistance gene (Steffan et al., 2004). Potentially, the reason for reduced interaction with CTBP1 (Kegel et al., 2002) is that the mutant protein is a better substrate for sumoylation, therefore causing it to be more rapidly released. Specific inhibition of Htt sumoylation may then be an effective approach to help cells survive the burden of mutant Htt that disruptively impacts cellular transcriptional programs (see below).

SREBF2 (SREBP)

The sterol response element binding transcription factor 2 (SREBF2) is a transmembrane protein that undergoes proteolytic release of its transcription factor domain from the membrane in response to reduced levels of sterols (Brown and Goldstein, 1997; Wang et al., 1994). In the nucleus, the soluble transcription factor domain activates the expression of genes encoding sterol biosynthetic enzymes. Thus, this protein senses the cellular levels of sterols and up-regulates their synthesis when low amounts are present in the cell.

Kaltenbach et al. (2007) identified an interaction of SREBF2 and Htt that was more robust when the nonexpanded polyglutamine protein was used in Y2H. This result is intriguing in light of the fact that studies have found that cholesterol biosynthetic enzyme mRNAs are reduced in cell and animal models of HD and in HD patients (Valenza et al., 2005, 2007a, 2007b). These results suggest that the presence of mutant huntingtin induces a down-regulation of mRNAs involved in cholesterol biosynthesis, and a weakened interaction with SREBF2 may be a part of the mechanism for this phenotype. One hypothesis is that normal Htt protein interaction with SREBF2 promotes the activity of SREBF2, and in cells containing mutant Htt a deficit in this interaction results in reduced expression of cholesterol-synthesizing gene products. Alternatively, some SREBF2 protein may be sequestered away from its normal function through interaction with mutant Htt.

Appropriate targeting of the impact of the defective interaction could be complicated. One approach to therapeutic intervention would be to increase cholesterol in the diets of HD patients. This has obvious caveats associated with atherosclerosis and inflammation risk and would require careful monitoring of cholesterol levels. However, circumvention of the reduced cholesterol biosynthesis in HD cells may be therapeutic if the ultimate sterol levels are the culprit.

REST/NRSF

Repressor element-1 transcription factor/neuron-restrictive silencing factor (REST/ NRSF) is a transcriptional repressor that maintains neural-specific genes in a repressed state in non-neural cell types (Chong et al., 1995; Schoenherr and Anderson, 1995). In neurons, wild-type huntingtin sequesters REST in the cytoplasm, thus allowing the expression of genes that are held in REST-dependent repressed states in other cell types. Mutant Htt is defective in the interaction with REST, and in HD models and patient brains REST accumulates in the nucleus (Zuccato et al., 2003). The aberrant nuclear presence of REST results in repression of prosurvival genes such as brain-derived neurotrophic factor (BDNF) and represents a strong candidate for therapeutic intervention.

In this case, a reduction in the amount of REST to decrease its presence in the nucleus would be predicted to be beneficial. This could potentially be accomplished by the introduction of small hairpin RNA constructs that target the REST transcript for degradation by the RNAi pathway (see Chapter 9, this volume). This “gene therapy” approach for such constructs will require developments in that field before it can be used in HD patients, but establishing the benefits of the strategy in mouse models of the disease could be done with current methodologies. As opposed to direct intervention at the level of this transcriptional repressor, the downstream gene targets it impacts may offer more straightforward therapeutic solutions.

In this context, the evidence of the detrimental consequences of defective BDNF delivery to striatal cells in HD is compelling (Zuccato and Cattaneo, 2007; Zuccato et al., 2001, 2005). Interestingly, BDNF knockout mice recapitulate the transcriptional changes in HD brain more closely than any HD mouse model tested (Strand et al., 2007). The body of work in this area argues that restoration of BDNF levels in the striatum may counteract the fundamental defect in HD brains. Administration of BDNF alone or in combination with other neurotrophic factors repressed by REST may circumvent the elevated levels of REST in the nucleus. However, the blood–brain barrier provides an obstacle to effective delivery of neurotrophic factors into the central nervous system. Recent work transplanting bone marrow cells that are transduced with the BDNF gene has shown this to be an effective way to deliver detectable amounts of BDNF in the brain (Makar et al., 2004, 2009). The recent developments in stem cell and induced pluripotent stem cell research may offer alternative cell types with advantages over bone marrow cells with which to deliver therapeutic factors such as BDNF. Alternatively, fusion of a protein transduction domain to BDNF has been shown to successfully facilitate transport of the factor across the blood–brain barrier, resulting in improved spatial learning and memory in a mouse model of Alzheimer’s disease (Zhou et al., 2008).

Importantly, Cattaneo and colleagues developed a BDNF promoter-based luciferase assay to identify small molecules that activate expression of BDNF (Rigamonti et al., 2007). They found three related compounds that at nanomolar levels could activate reporter and endogenous BDNF levels, as well as importantly increase expression of other REST/NRSF gene targets. This suggests that the compounds target REST/ NRSF generally and not solely the BDNF promoter. This screening platform has thereby successfully identified compounds showing therapeutic promise, and indeed one of these compounds has been shown to be able to rescue toxicity in an HD cell model.

PPARγ

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is important for adipocyte differentiation (Tontonoz et al., 1995). Hypolipidemic drugs and other PPAR activators, including naturally occurring polyunsaturated fatty acids, promote the differentiation of PPARγ-expressing cells in a dose-dependent manner, and retroviral expression of PPARγ is sufficient to cause fibroblast lines to become preadipocytes (Tontonoz et al., 1994). PPARγ is also expressed in other tissues, including brain (Heneka and Landreth, 2007), and has been shown to have neuroprotective effects (Bordet et al., 2006; Heneka et al., 2007).

PPARγ has been shown to interact with Htt by two independent groups (Futter et al., 2009; Kaltenbach et al., 2007). In a fly model of degeneration, heterozygosity for a loss-of-function allele for PPARγ was a suppressor, suggesting that the interaction with mutant Htt is a detrimental one that can be rescued by decreasing the levels of PPARγ (Kaltenbach et al., 2007). However, coimmunoprecipitation experiments show wild-type Htt more strongly interacting with PPARγ (Futter et al., 2009), suggesting that the mutant protein is defective in its interaction with the receptor. This is more in line with multiple studies showing that PPARγ activation is important for mitochondrial biogenesis, and thus reductions in PPARγ may be expected to be toxic.

Two recent studies have provided additional evidence for an important contribution of PPARγ in HD. The PPARγ coactivator 1α (PGC-1α) transcriptional coactivator is observed to be transcriptionally repressed in cells expressing mutant Htt (Cui et al., 2006). Crossing mutant Htt mice with PGC-1α knockout mice led to enhanced neurodegeneration, whereas overexpression of PGC-1α in a mutant Htt striatal cell line partially suppressed toxicity. Furthermore, a second study showed that HD mice are hypothermic, and PGC-1α-regulated genes are reduced in both brown adipose tissue and the striatum (Weydt et al., 2006). This group additionally observed PGC-1α transcriptional deficits in HD patient striatum, suggesting this defect manifests in the disease as it does in mutant Htt model systems.

Based on its role as a coactivator for PPARγ, the reduced PGC-1α function suggests that activation of PPARγ may be of therapeutic benefit in HD. This is additionally supported by multiple studies describing beneficial effects of PPARγ agonists in a variety of neurodegenerative diseases, including Alzheimer’s disease (Inestrosa et al., 2005; Watson et al., 2005), amyotrophic lateral sclerosis (Kiaei et al., 2005), multiple sclerosis (Watson and Craft, 2006), and Parkinson’s disease (Breidert et al., 2002; Quinn et al., 2008; Schintu et al., 2009). The existence of agonists and antagonists for PPARγ allows for direct experiments into its role in mutant Htt toxicity.

An agonist of PPARγ, rosiglitazone, has been shown to have protective effects in a mutant Htt striatal cell line challenged by thapsigargin exposure (Quintanilla et al., 2008). Addition of thapsigargin, a disruptor of calcium homeostasis, to mutant Htt cells resulted in mitochondrial dysfunction as indicated by elevated reactive oxygen species production and a decrease in the mitochondrial membrane potential. This effect of thapsigargin was blocked by pretreatment with rosiglitazone, suggesting that PPARγ activation could protect cells from the mitochondrial dysfunction. Importantly, the authors showed that the effects were abrogated if an antagonist of PPARγ, GW9662, was also added.

Finally, the interaction of wild-type Htt with PPARγ is likely reduced in mutant Htt-containing cells. Because mutant Htt also represses the levels of PGC-1α, the activity of PPARγ is blunted on two fronts by the mutant protein. Use of activating PPARγ ligand mimetics should prove effective in overcoming both defects and thus may be promising as therapeutic molecules for the treatment of the disease.

Nuclear Hormone Receptors

Specific interactions between multiple nuclear hormone receptors and Htt have been reported. Kaltenbach et al. (2007) showed an interaction between the retinoic acid receptor α (RARα) and Htt using Y2H. Futter et al. (2009) demonstrated coimmunoprecipitation of the liver X receptor α (LXRα), vitamin D receptor (VDR), and thyroid hormone receptor α (THRα) with Htt. Interactions with these nuclear hormone receptors were stronger with wild-type Htt, and reporters and endogenous targets of LXRα transcriptional activity showed coactivation by wild-type Htt. Mutant Htt did not confer coactivation, leading to the conclusion that the polyglutamine tract expansion results in a loss of this activity.

These results are intriguing in combination with the demonstration of interactions between Htt and N-CoR (Boutell et al., 1999; Kaltenbach et al., 2007) and nuclear receptor coactivator 3 (N-CoA3) (Kaltenbach et al., 2007). N-CoR binds to unliganded nuclear hormone receptors and represses expression of their target genes, whereas N-CoA binds to liganded receptors and activates the expression of their target genes. This supports the model of mutant Htt impacting the expression of hormone-responsive genes by independently determined interactions with the specific and general factors involved in their regulation. The evidence suggests that wild-type Htt is a coactivator of multiple nuclear hormone receptors, whereas mutant Htt is at least defective in coactivation and also impacts the normal repression of these receptors by inducing the mislocalization of their main corepressor, N-CoR, to the cytoplasm.

Thus, this family of transcription-related interaction partners potentially provides one of the most amenable therapeutic targets for HD. This is because of readily available agonists (and cognate ligands) for these factors. Their ligand-binding mechanism of action makes the nuclear hormone receptors an inherently “druggable” group of transcription factors. Additionally, based on the results showing differential interaction and resultant consequences with wild-type and mutant Htt, the use of agonists is likely to restore some of the lost regulation that occurs in the presence of mutant Htt. For these reasons, the use of nuclear hormone receptor agonists may represent tractable therapeutic approaches based on identified protein interactions between Htt and transcription-related proteins.

POTENTIAL DETRIMENTAL INTERACTION PARTNERS OF MUTANT HUNTINGTIN

Of the 58 interactions between transcription-related proteins and Htt reported in the literature, 19 include evidence of a detrimental effect of the interaction. Included among these is the interaction of Htt with itself, based on the evidence for a direct transcriptional role of Htt in the cell (Benn et al., 2008; Zhai et al., 2005). The mechanisms by which mutant Htt can interact with a transcriptional protein with harmful consequences can be generally thought of as one of three nonexclusive possibilities. First, mutant Htt may sequester a prosurvival transcription factor in the cytoplasm or within an intranuclear inclusion where it is unavailable to perform its function. Second, mutant Htt may promote the activity of an apoptotic/cell death-inducing transcription factor. Third, the protein may promote the toxic impact of mutant Htt on the cell. In the following discussion we will attempt to suggest which of these is in play for a given interaction partner based on the evidence to date.

MEF2D

The myocyte enhancer factor 2D (MEF2D) is a transcriptional activator with an established role in commitment of myogenic lineages (Breitbart et al., 1993). Importantly, the MEF2 family of transcription factors has also been shown to have prosurvival roles in neurons (Gong et al., 2003; Ikeshima et al., 1995; Mao et al., 1999; Okamoto et al., 2000, 2002). The regulation of these transcription factors is mediated by a variety of inputs, including phosphorylation (Gong et al., 2003) and antagonistic binding of corepressor proteins that inhibit the expression of MEF2 transcriptional targets.

Using the Y2H method, it was observed that MEF2D interacts with Htt, and this interaction decreases with a longer polyglutamine tract Htt (Kaltenbach et al., 2007). Further, in the same study, heterozygous loss-of-function mutations in Mef2 suppressed the phenotype caused by expression of a mutant Htt fragment in the Drosophila eye. This latter result argues that the interaction between mutant Htt and MEF2D is detrimental and that a moderate reduction of the Mef2 protein level is beneficial for mutant Htt-containing cells, presumably by decreasing the harmful effect of the mutant Htt interaction with Mef2.

To establish MEF2D as a therapeutic target, the mechanism of the harmful interaction with Htt will need to be elucidated. The suppression of mutant Htt toxicity by a heterozygous Mef2 loss-of-function allele suggests that mutant Htt may promote elevated expression of Mef2 target genes. The neurons perhaps undergo apoptosis in response to inappropriately expressed factors that are necessary and beneficial during development or at particular levels of expression but trigger tumor suppressor pathways when maintained or supplemented by the action of mutant Htt in an inappropriate context. Alternatively, mutant Htt may mediate the assembly of complexes of transcriptional repressors at MEF2D sites, and the reduction of MEF2D levels reduces the recruitment of these to important prosurvival genes. Until the phenotypic consequences of mutant Htt on MEF2D are better understood, it is unclear what intervention approach would be beneficial.

Sp1 and Sp3

The specificity transcription factor 1 (Sp1) and specificity transcription factor 3 (Sp3) are important transcriptional activators that target particular genes for expression (Cook et al., 1999). In the particular case of Sp1, it is observed to interact with multiple other transcription factors (see Figure 3.1) and plays a major role in gene expression by recruiting the basal transcription machinery in the form of transcription factor IID to its target genes (Pugh and Tjian, 1990). Sp1 also contains a glutaminerich region (Courey and Tjian, 1988).

The evidence of an interaction between Sp1 and Htt came initially from two sources. Dunah et al. (2002) recognized that mRNA expression arrays of HD mice had changes in genes that contained recognition sites for Sp1 binding. They demonstrated an interaction between Htt and Sp1 and showed that overexpression of Sp1 rescues mutant Htt toxicity and repression at the dopamine D2 receptor gene. Additionally, they showed that mutant Htt prevents Sp1 from binding to DNA. Similarly, Li et al. (2002) initiated another study when they noticed that many genes that were differentially expressed in HD cell lines and mouse models harbored Sp1 recognition motifs. They observed that polyglutamine expansion enhances the interaction of N-terminal Htt with Sp1, and whereas soluble mutant Htt interacts with Sp1, aggregated mutant Htt does not. Using the nerve growth factor receptor gene promoter as a reporter, they found that mutant Htt represses Sp1 transcription, and Sp1 overexpression also suppressed toxicity in their models. Later work further demonstrated direct mutant Htt repression of Sp1-mediated transcription in an in vitro transcription system (Zhai et al., 2005).

Because of the central importance of Sp1 in the expression of a large number of genes, therapeutic targeting to relieve Sp1 of repression by mutant Htt should be an effective approach to alleviating the transcriptional dysregulation aspect of the disease. Activation of Sp1 or increasing its levels would be one approach that could counteract the influence of mutant Htt. Studies have demonstrated that Sp1 is activated by phosphorylation regulated by several signal transduction cascades (Chuang et al., 2008; Horovitz-Fried et al., 2007; Merchant et al., 1999; Tan and Khachigian, 2009; Zheng et al., 2000, 2001), suggesting that growth factors or stimulants of these pathways could be used to increase Sp1 activity. Sp1 is also sumoylated, and this modification results in relocalization to the cytoplasm and enhanced degradation of Sp1 by the proteasome (Wang et al., 2008). Hence, inhibition of Sp1 sumoylation may increase its levels and help offset the problematic interaction of the protein with mutant Htt (see below).

CBP (CREBBP)

The CBP plays essential roles in homeostasis and other processes based on its bridging of transcription factor recognition with chromatin remodeling (Kalkhoven, 2004). The interaction of CBP with CREB, as well as the determination of its transcriptional activation function, established it as having a central role in the cell (Chrivia et al., 1993). CBP is a histone acetyltransferase (Bannister and Kouzarides, 1996; Ogryzko et al., 1996) whose modification of histones results in the transcriptional activation of genes.

The interaction of CBP with Htt has been demonstrated by numerous groups. CBP was found to be trapped in expanded polyglutamine aggregates in a transfected cell line only when its own 19-glutamine stretch was present in the protein (Kazantsev et al., 1999). Htt exon 1 interacts with CBP in vitro, the interaction is enhanced in expanded polyglutamine-containing exon 1, and CBP colocalizes with intranuclear Htt inclusions in HD transgenic mice (Steffan et al., 2000). Htt exon 1 can bind to and inhibit the acetyltransferase domain of CBP, as well as that of other acetyltransferases (Steffan et al., 2001). CBP is depleted from its normal nuclear location by mutant Htt in cell culture, HD transgenic mice, and in human HD postmortem brain; expanded polyglutamine Htt represses CBP-activated transcription; and overexpression of CBP rescues polyglutamine-induced neuronal toxicity (Nucifora et al., 2001). A high-throughput Y2H screen found CBP as an interactor of Htt (Kaltenbach et al., 2007). Finally, CBP was recently shown to acetylate mutant Htt, and this modification targets it for degradation by autophagy (Jeong et al., 2009). This last result, in contrast with the other lines of evidence, suggests that the interaction of CBP and mutant Htt may actually be beneficial (see below).

The preponderance of evidence suggests that the interaction between Htt and CBP is detrimental to cells because Htt inhibits CBP function. Thus, the prevention of the interaction of Htt with this critical transcriptional coactivator would most likely prove beneficial. However, this is difficult to accomplish by small molecule inhibitors of the interaction because both the polyQ region and the acetyltransferase domain of CBP can mediate seemingly independent interactions with Htt, suggesting the interaction motifs may include two (or more) surfaces of CBP. Activation of CBP or increasing its levels would be additional strategies to overcome the CBP deficiency caused by mutant Htt.

An alternative approach to activating CBP is to inhibit the enzymes that counteract its activity. Such enzymes, the HDACs, are amenable to targeting by small molecules. The inhibition of HDACs enriches the amount of acetylated histones and nonhistone proteins, accomplishing the same effect as would be expected for increasing the activity or levels of CBP or other acetyltransferase enzymes. HDAC inhibitors have been explored as antitumor therapeutics based on their differentiation-inducing effects (Bolden et al., 2006; Botrugno et al., 2009). More importantly, a number of studies have established a therapeutic benefit of HDAC inhibitors in cell and animal models of HD (Bates et al., 2006; Hockly et al., 2003; Hughes et al., 2001; McCampbell et al., 2001; Pallos et al., 2008; Parker et al., 2005; Steffan et al., 2001). Therefore, modulation of the acetylation state of key proteins is a therapeutic strategy with great potential in the treatment of HD that may restore the deficiency caused by lost CBP activity imparted by its interaction with mutant huntingtin.

Of note, a direct consequence of Htt on CBP has been described in multiple studies, but only one emphasizes a reciprocal impact of CBP on mutant Htt (Jeong et al., 2009). The authors show that CBP acetylates mutant Htt, and this modification causes autophagic clearance of the toxic protein. This suggests a beneficial effect of CBP binding to mutant Htt, with the interaction leading to reduced mutant Htt in the cell. Overexpression of CBP rescues toxicity in this model, as does RNAi knockdown of an HDAC enzyme whose overexpression conversely decreases mutant Htt acetylation. In HD, the binding of mutant Htt to CBP may be a directed process to cause its degradation, but endogenous levels of the two proteins result in CBP becoming sequestered and inactivated by the interaction. Therapeutic effects of deacetylase inhibition could rescue toxicity through multiple targets in a way that is independent of the biological role of the actual protein interaction—be it beneficial or detrimental.

N-CoR and mSin3a

The N-CoR was identified by its binding to unliganded nuclear receptor heterodimers (Horlein et al., 1995). Unliganded nuclear hormone receptors had been observed to repress transcription, and binding of N-CoR (or the closely related SMRT [Chen and Evans, 1995]) was found to mediate this repression. This most often occurs through the recruitment of complexes containing HDAC activity (Jepsen and Rosenfeld, 2002). N-CoR has been shown to potently regulate such nuclear receptors as PPARγ and VDR (Abedin et al., 2009). Hence, the function of N-CoR in the cell appears to center around maintaining genes that are responsive to hormone/vitamin cues in a repressed state in the absence of their signaling molecules. However, it has recently been shown that at least one ligand can mediate corepression when binding to its receptor in a heterodimeric context, causing the unliganded partner receptor to bind N-CoR or another corepressor (Sanchez-Martinez et al., 2008).

In HD, the function of N-CoR is disrupted. A Y2H study identified a specific interaction of the C-terminal region of N-CoR with Htt that was polyglutamine length-dependent (Boutell et al., 1999). The authors went on to demonstrate that N-CoR was exclusively cytoplasmic in HD cortex and caudate, whereas in control brain the protein is present in both the cytoplasm and the nucleus. This suggests a relocalization of N-CoR in mutant Htt cells, presumably because of an inappropriate interaction with the mutant protein.

A second Y2H study independently identified an interaction between Htt and N-CoR (Kaltenbach et al., 2007). Intriguingly, using their mutant Htt-dependent fly retinal degeneration model, they identified N-CoR as a hemizygous loss-of-function suppressor of toxicity. One possibility that would explain this counterintuitive result is that the relocalization of N-CoR in HD brain confers toxicity potentially through trapping a partner protein in the cytoplasm, and reduction of N-CoR levels decreases this sequestration. Alternatively, N-CoR elicits some as yet unrealized toxic response in the cytoplasm. Further work will be required to establish whether either of these mechanisms may have a role in HD.

One of N-CoR’s partner proteins, mammalian SIN3 (yeast switch independent 3) homologue A (mSin3a), forms transcription-repressing complexes in combination with HDAC1/2 enzymes (Laherty et al., 1997). Boutell et al. (1999) saw the relocalization of mSin3a exclusively to the cytoplasmic compartment in HD patient samples, with the only exceptions being ~5% of neuronal intranuclear inclusions where mSin3a was also observed to be present. An independent study described a polyglutamine length-dependent interaction between mSin3a and Htt (Steffan et al., 2000). Studies to establish the effects of changes in the levels of N-CoR and mSin3a are required before the potential interplay of their redistribution in mutant Htt cells can be understood. However, based on the existing evidence, one can speculate that the trapping of mSin3a in the cytoplasm is a detrimental consequence of mutant huntingtin’s enhanced interaction with the N-CoR/mSin3a complex. Reduction of N-CoR levels reduces mSin3a association with mutant Htt and thus maintains some of its presence in the nucleus, allowing it to carry out enough of its nuclear function to reduce the defect.

If this mechanism is correct, targeting of the consequences of this interaction by HDAC inhibition could have beneficial effects. As mentioned previously, the transcriptional repression complexes that contain N-CoR and mSin3a frequently contain HDAC enzymes, and thus their redistribution to the cytoplasm may either sequester HDACs in the cytoplasm or result in an accumulation of HDAC enzymes in the nucleus. As a result of the observation of the toxicity-rescuing effects of HDAC inhibition in a number of HD models (Bates et al., 2006; Hockly et al., 2003; McCampbell et al., 2001; Pallos et al., 2008; Parker et al., 2005; Steffan et al., 2001), the latter mechanism seems likely, but the inappropriate presence of HDACs in the cytoplasm could also have toxic consequences, such as the stabilization of mutant Htt (Jeong et al., 2009). Again, irrespective of the mechanism, HDAC inhibition has potential for therapeutic rescue based on these interactions with mutant Htt.

p53

The tumor suppressor p53 is mutated in a large number of cancer cells (Malkin et al., 1990; Srivastava et al., 1990; Vogelstein, 1990). The mutations largely prevent or reduce binding to DNA, leading to an inability of the protein to regulate transcription of its target genes (Kern et al., 1991a, 1991b). p53, through its transcriptional activity, also plays an important role in promoting neuronal apoptosis (Ra et al., 2009; Uo et al., 2007). The neuronal apoptotic role of p53 and its putative modulation by an interaction with mutant Htt is of particular interest.

An initial description of an interaction between Htt and p53 found in vitro that there was no preference of p53 for expanded versus nonexpanded polyglutamine (Steffan et al., 2000). The authors also observed the presence of p53 in mutant Htt aggregates, as well as the ability of Htt to repress transcription of p53-dependent genes using luciferase reporters. Interestingly, a gene that is repressed by p53 could, in a p53 knockout cell line, be repressed by a mutant Htt fragment to a much greater degree than by a wild-type Htt fragment. This suggests that Htt may exacerbate p53 function independently of their physical association.

A later study of the interaction between Htt and p53 established the consequences of their interaction more fully (Bae et al., 2005). The authors showed an interaction between mutant Htt and p53 that is not observed with a second expanded polyglutamine protein. Further, mutant Htt increases p53 nuclear abundance and its transcriptional activity. p53 levels are also increased in transgenic mice and HD patient brains. Most importantly, these authors show that p53 inhibition by genetic deletion, RNAi, and pfithrin-α treatment all lead to reduced cytotoxicity in HD cells.

The results of Bae et al. (2005) support the idea that p53 inhibition could be a therapeutic intervention in HD. Inhibition of a central tumor suppressor such as p53 is not an ideal approach for obvious reasons, but if neural-specific delivery of a small molecule inhibitor or RNAi-mediated knockdown can be accomplished, this may be a useful approach to not only HD but also to other neurodegenerative diseases as well. Chemical compounds that inhibit p53 have been developed and should be investigated in HD models (Nayak et al., 2009).

Sumoylation

The attachment of the SUMO to the lysine side chains of proteins can have varied consequences on the substrate protein (Hay, 2005; Johnson, 2004). In terms of transcription-related consequences, sumoylation of proteins can cause translocation into the nucleus, stabilization of the protein, or its degradation. These effects are likely mediated by one of three mechanisms. Attachment of SUMO to a protein permits its recognition by SUMO-binding proteins, causing the substrate protein to be targeted by the relevant activity. A second possibility is that the modification by SUMO competes with an alternative modification at a given lysine residue. For example, attachment of ubiquitin to a particular lysine of a protein may promote its degradation, whereas attachment of SUMO to the same residue prevents both the attachment of ubiquitin and the resultant degradation. Third, attachment of SUMO may modulate the post-translational modification of other sites on the protein, leading to their enhancement or inhibition.

The interaction of SUMO with Htt is through covalent attachment of SUMO to one or more of three N-terminal lysine residues of mutant Htt (Steffan et al., 2004; Subramaniam et al., 2009). This modification results in the stabilization of mutant Htt, and sumoylation promotes cytotoxicity. Steffan et al. (2004) also showed that sumoylation of mutant Htt enhanced repression of a luciferase reporter driven by a mutant Htt-responsive promoter and that hemizygosity of the SUMO homologue Smt3 reduced neurodegeneration as a result of mutant Htt in flies. These results suggest that direct prevention of Htt sumoylation may be an effective therapeutic target and, further, that a general reduction of the cellular SUMO1 pool may prove beneficial. Subsequent studies have confirmed that SUMO plays a key role in the cytotoxicity of mutant Htt (Subramaniam et al., 2009).

A strategy incorporating the general inhibition of sumoylation is also supported by the effect of sumoylation on several of the interaction partners of Htt presented here. coREST, a corepressor with REST, is sumoylated, and, in the absence of SUMO1, coREST repressive activity is decreased (Muraoka et al., 2008). CBP modification by SUMO1 reduces CBP transcriptional activity by promoting an interaction with a transcriptional corepressor (Kuo et al., 2005). One study (Spengler and Brattain, 2006) found that Sp1 is sumoylated, and this inhibits its transcriptional activity; a second study (Wang et al., 2008) showed that sumoylation of Sp1 led to its cytoplasmic localization and interaction with a proteasome component, resulting in its degradation. Sumoylation of Sp3 causes it to have transcriptional repressing activity by inducing proximal heterochromatic-based silencing (Stielow et al., 2008). SREBF2 is also sumoylated, and the modification results in reduced transcriptional activity of the factor (Hirano et al., 2003).

Based on the toxicity-promoting role of SUMO modification of mutant Htt and the likely exacerbating inhibitory effects it has on multiple protein partners of Htt, inhibition of sumoylation is a strong candidate for rescuing mutant Htt toxicity. Recently, an inhibitor of the initial step in the sumoylation enzymatic cascade has been identified. Ginkgolic acid and the analogous anacardic acid were shown to bind to the SUMO E1 enzyme and block the creation of the E1-SUMO intermediate (Fukuda et al., 2009). Therefore, these compounds may provide a way to reduce overall sumoylation within the cell. In cells with mutant Htt, therapeutic intervention working on multiple proteins that are SUMO substrates could potentially suppress multiple defects caused by mutant Htt.

TRANSCRIPTION PROTEIN INTERACTION SUMMARY

In conclusion, the interaction of Htt with transcription-related proteins consists of both normal cellular associations and inappropriate mutant-specific protein complexes. Strategies to promote the interactions that wild-type Htt engages in within the context of HD cells may restore lost functions of critical importance to the cell. On the other hand, the inhibition of interactions of proteins with mutant Htt may suppress harmful impacts of the mutant protein. Targeting of such interactions with small-molecule therapeutics is nontrivial because of the large relative size of the interacting surfaces of two proteins. Hence, the alternative approach of increasing the levels of a prosurvival interaction partner or inhibiting the activity or amounts of a detrimental protein interactor may more readily accomplish the same goal. Nuclear hormone receptor agonists, HDAC inhibitors, and sumoylation inhibitors are three strategies that appear to have great promise and will hopefully fulfill that potential in being developed into therapeutics for HD. Finally, the value of knowledge concerning protein-interacting partners such as those transcription factors discussed here goes beyond strategies designed to target these specific proteins. Ultimately, information about the specific pathways that lie downstream of these factors (e.g., sterol biosynthesis) can also provide inroads into therapeutic candidates.

In this chapter we have attempted to outline the ways in which protein interaction discovery can lead us not only into thinking about pathogenic mechanisms in HD but also how protein interactions can lead to specific targets and thereby strategies for therapeutic intervention. Selecting from the breadth of protein interactions and pathogenic mechanisms involved in HD, we focused on one central aspect of HD pathobiology, that of transcriptional dysregulation. However, the principles of using interacting proteins as a means of understanding disease pathways in terms of drug discovery is generally applicable to other implicated processes. In the past decade, the field of protein interaction studies has exploded from single investigator/single target-driven activities to highly automated, massively parallel proteome-scale research enterprises. The proliferation of complex interaction networks being reported in the literature for humans (as well as other organisms of biological and medical interest) is exciting and accelerating. Many of these studies are unbiased in nature in that they focus on the broad class of human proteins rather than specific types of proteins, such as huntingtin. The two large-scale HD-specific protein interaction networks constructed to date provide an opportunity to understand targets not just in the context of binary relationships but rather at a network level. Computational methods that will allow us to properly mine the data contained in these networks are just beginning to be developed, and they should soon help us identify the signals that exist among the noise in these complex datasets. It is clear that HD is highly complex in the number and nature of biological pathways that have been demonstrated to be perturbed by the expression of the mutant huntingtin protein. Ultimately, a comprehensive understanding of this complex disease and the volumes of information being generated by its study will require increasingly complex methods of analysis to realize fully the development of comprehensive therapeutic strategies.

ACKNOWLEDGMENTS

We thank the Hereditary Disease Foundation, CHDI Foundation Inc., and the National Institutes of Health for their support.

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