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| 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
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| 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.
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| Overall design |
RNA-seq on mouse striatum injected with PBS, LPS or IL-4
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| 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 |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA540978 |
| SRA |
SRP194918 |
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