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Series GSE130683 Query DataSets for GSE130683
Status Public on Aug 12, 2019
Title Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer.

Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout.

Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response.

Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.
Overall design RNA-seq on mouse striatum injected with PBS, LPS or IL-4
Contributor(s) George S
Citation(s) 31419995
NIH grant(s)
Grant ID Grant title Affiliation Name
R21 NS093993 Does Microglial Activation Influence Propagation of Alpha-synuclein Pathology VAN ANDEL RESEARCH INSTITUTE Patrik Brundin
Submission date May 03, 2019
Last update date Aug 26, 2019
Contact name Sonia George
Organization name Van Andel Research Institute
Street address 333 Bostwick Ave
City Grand Rapids
State/province MI
ZIP/Postal code 49503
Country USA
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (17)
GSM3747615 1010 PBS
GSM3747616 1004 PBS
GSM3747617 630 PBS
BioProject PRJNA540978
SRA SRP194918

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Supplementary file Size Download File type/resource
GSE130683_LPS_IL4_supplemental_data.xlsx 20.1 Mb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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