AUTHOR=Sarkar Souvarish , Dammer Eric B. , Malovic Emir , Olsen Abby L. , Raza Syed Ali , Gao Tianwen , Xiao Hailian , Oliver Danielle L. , Duong Duc , Joers Valerie , Seyfried Nicholas , Huang Meixiang , Kukar Thomas , Tansey Malú G. , Kanthasamy Anumantha G. , Rangaraju Srikant 

TITLE=Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00033

DOI=10.3389/fimmu.2020.00033

ISSN=1664-3224

ABSTRACT=<p>Alpha-synuclein (αSyn<sub>Agg</sub>) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSyn<sub>Agg</sub>-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, αSyn<sub>Agg</sub> induced robust pro-inflammatory activation (increased expression of 864 genes including <italic>Irg1, Ifit1</italic>, and <italic>Pyhin</italic>) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSyn<sub>Agg</sub> 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 <italic>in vitro</italic> studies suggested that αSyn<sub>Agg</sub> partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSyn<sub>Agg</sub> induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSyn<sub>Agg</sub> were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/<italic>Grn</italic>). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSyn<sub>Agg</sub> in microglia <italic>in-vivo</italic> and is expressed by microglia in post-mortem PD brain, congruent with our <italic>in vitro</italic> findings.</p><p><bold>Conclusion:</bold> Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.</p>