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Molecular Signatures of Neuroinflammation Induced by ?Synuclein Aggregates in Microglial Cells.

ABSTRACT: Alpha-synuclein (?SynAgg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of ?SynAgg-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, ?SynAgg 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, ?SynAgg 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 ?SynAgg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that ?SynAgg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by ?SynAgg 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 ?SynAgg 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 ?Syn-mediated neuroinflammation in PD and other synucleinopathies.

SUBMITTER: Sarkar S

PROVIDER: S-EPMC7006296 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells.

Sarkar Souvarish S Dammer Eric B EB Malovic Emir E Olsen Abby L AL Raza Syed Ali SA Gao Tianwen T Xiao Hailian H Oliver Danielle L DL Duong Duc D Joers Valerie V Seyfried Nicholas N Huang Meixiang M Kukar Thomas T Tansey Malú G MG Kanthasamy Anumantha G AG Rangaraju Srikant S

Frontiers in immunology 20200131

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 acti ...[more]

PMID: 32082315

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Dataset Information

Molecular Signatures of Neuroinflammation Induced by ?Synuclein Aggregates in Microglial Cells.

Publications

Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells.

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