The persistent and multidimensional microglial response to pathological alpha-synuclein aggregation
Parkinson's Disease, the second most common neurodegenerative disease, affects approximately 1 million people in the USA with 60,000 newly diagnosed people each year. Pathologically, PD is characterized by the presence of proteinaceous alpha-synuclein (Îł-syn) inclusions (Lewy bodies) and the progressive loss of the nigrostriatal dopamine (DA) neurons. While the exact cause of PD remains unknown, mounting evidence has suggested that neuroinflammation may play a significant role in PD progression. The pathological features of PD can be recapitulated in vivo using the Îł-syn preformed fibril (PFF) model of synucleinopathy in rats. Specifically, in association with accumulation of phosphorylated Îł-syn (pSyn) inclusions in the SNpc, microglia increase soma size and MHC-II expression. This microglial response parallels pSyn inclusion formation, peaking at 2 months following intrastriatal PFF injection, months prior to the SNpc degeneration observed in the model. The overarching question of this dissertation is: does the microglial response to pathological Îł-syn accumulation contribute to degeneration? In Aim 1 of this dissertation an inhibitor of colony stimulating factor 1 receptor (CSF1R) was used to partially deplete microglia within the context of the Îł-syn PFF rat model in order to determine whether degeneration of the nigrostriatal system can be attenuated. Despite significant microglial depletion, increased soma size and expression of major-histocompatibility complex-II (MHC-II) on microglia within the Îł-syn inclusion bearing substantia nigra pars compacta (SNpc) was maintained. Further, partial microglia depletion did not impact degeneration of dopaminergic neurons in the SNpc. Paradoxically, long term partial microglial depletion increased the soma size of remaining microglia in both control and PFF rats was associated with widespread MHC-IIir expression in extranigral regions. These results suggest that partial microglial depletion is not a promising anti-inflammatory therapeutic strategy for PD and that this approach may induce a heightened proinflammatory state in remaining microglia. Aim 2 of this dissertation built on a previous study RNA-Seq dataset that identified multiple upregulated innate and adaptive immune transcripts in the inclusion bearing SNpc in the PFF model. Complementary approaches of fluorescent in situ hybridization (FISH) and droplet digital PCR (ddPCR) were used. FISH results identified an a-syn aggregate associated microglial (a-SAM) phenotype that is characterized by upregulation of CD74, CXCl10, RT1-A2, GRN, CSF1R, Tyrobp, C3, C1qa and Fcer1g. ddPCR results identified additional neuroinflammatory genes, Cd4, Stat1, Casp 1, Axl and IL18, that are significantly upregulated in inclusion bearing nigral tissue. Collectively these findings implicate that the deposition of pathological Îł-syn inclusions in the SNpc is associated with perturbations in immune functions related to complement, inflammasome and T cell activation, phagocytosis, and interferon gamma signaling. Collectively, the findings of these dissertation experiments demonstrate that the microglial response to pathological Îł-syn aggregation is persistent and multifaceted. This comprehensive understanding of the multidimensional response of microglia to pathological Îł-syn aggregates may help to uncover novel therapeutic targets that could facilitate future anti-inflammatory, disease-modifying strategies for PD.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Stoll, Anna C.
- Thesis Advisors
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Sortwell, Caryl E.
- Committee Members
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Dorrance, Anne
Bailie, Marc
Rockwell, Cheryl
Bernstein, Alison
- Date
- 2022
- Subjects
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Neurosciences
Immunology
Parkinson's disease
Research
Brain--Diseases
Alpha-synuclein
Nervous system--Degeneration
Microglia
Inflammation
- Program of Study
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Pharmacology and Toxicology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xxi, 207 pages
- ISBN
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9798841789239
- Permalink
- https://doi.org/doi:10.25335/zbd8-fj35