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Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells

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Last modified
  • 05/14/2025
Type of Material
Authors
    Souvarish Sarkar, Harvard Medical SchoolEric Dammer, Emory UniversityEmir Malovic, Iowa State UniversityAbby L. Olsen, Harvard Medical SchoolSyed A. Raza, Emory UniversityTianwen Gao, Emory UniversityHailian Xiao, Emory UniversityDanielle L. Oliver, University of FloridaDuc Duong, Emory UniversityValerie Joers, University of FloridaNicholas Seyfried, Emory UniversityMeixiang Huang, Emory UniversityThomas Kukar, Emory UniversityMalu Tansey, Emory UniversityAnumantha G. Kanthasamy, Iowa State UniversitySrikant Rangaraju, Emory University
Language
  • English
Date
  • 2020-01-31
Publisher
  • Frontiers Media
Publication Version
Copyright Statement
  • © Copyright © 2020 Sarkar, Dammer, Malovic, Olsen, Raza, Gao, Xiao, Oliver, Duong, Joers, Seyfried, Huang, Kukar, Tansey, Kanthasamy and Rangaraju.
License
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1664-3224
Volume
  • 11
Start Page
  • 33
End Page
  • 33
Grant/Funding Information
  • This work was supported by Emory Alzheimer's Disease Research Center Grant P50 AG025688, Alzheimer's Association (SR #37102), NINDS (K08-NS099474-1) and Emory Neuroscience NINDS Core facilities (P30 NS055077) to SR; NINDS (NS100090) and NIEHS (ES026892) to AK; National Institutes of Health (NIH) Grants (R01NS093362, R01NS105971), a New Vision Award (Donors Cure Foundation), an Emory Alzheimer's Disease Center Pilot Grant P50AG025688, the Alzheimer's Drug Discovery Foundation, the Association for Frontotemporal Degeneration (ADDF/AFTD), and the Bluefield Project to Cure Frontotemporal Dementia to TK; National Institutes of Health (NIH) fellowship (Training in Translational Research in Neurology, 2T32NS007480-16), NIH Udall pilot grant (1P50NS098685) and NIH Yerkes Pilot grant (P51 OD011132) to VJ National Institutes of Health (NIH) Grants (5R01NS092122, 1RF1AG051514, 1RF1AG057247), the ADDF/AFTD, and the Michael J. Fox Foundation for Parkinson's Research to MT.
Supplemental Material (URL)
Abstract
  • Alpha-synuclein (αSynAgg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSynAgg-induced immune activation are poorly defined. We performed quantitative proteomics by mass spectrometry coupled with PCR, immunohistochemical and functional validations studies to define the molecular characteristics of alpha synuclein mediated microglial activation. In mouse microglia, αSynAgg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1, and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSynAgg decreased expression several proteins (including Cdc123, Sod1, and Grn), which were predominantly cytosolic and involved in metabolic, proteasomal and lysosomal mechanisms. Pathway analyses and confirmatory in vitro studies suggested that αSynAgg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSynAgg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSynAgg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/Grn). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSynAgg in microglia in-vivo and is expressed by microglia in post-mortem PD brain, congruent with our in vitro findings. Conclusion: Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.
Author Notes
Keywords
Research Categories
  • Biology, Neuroscience

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