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Control (healthy) iPSC-derived astrocytes treated with: Media (control), TNFa 100ug/ml, Monomeric aSYN 10uM, or Fibril aSYN 10uM

ABSTRACT: The overall goal was to identify changes in gene expression following treatment with TNFa, monomeric, or fibril aSYN compared to control (untreated). Alpha-synuclein (αSYN) protein has been observed in reactive astrocytes in PD patients’ brains, raising the question of how αSYN, neuroinflammation, and astrocytes interact in PD pathogenesis. Here, we examined the cellular changes triggered by tumor necrosis factor alpha (TNFα) and different αSYN species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNFα displayed a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the NF-kB pathway, and release of pro-inflammatory cytokines, whereas those treated with high molecular weight αSYN fibrils acquired a reactive antigen (cross-)presenting phenotype with upregulation of MHC genes and increased HLA-DR/DQ/DP and HLA-F molecules at the cell surface. Surprisingly, cell surface location of MHC proteins was abrogated by larger F110 fibrils polymorph, despite the upregulation of MHC genes. A proteomics investigation further confirmed a direct interaction between astrocytic MHC proteins and αSYN fibril peptides. Interestingly, TNFα and αSYN fibrils competed to drive the astrocyte immune reactive response. The astrocyte immune responses were accompanied by an impaired ATP-generating mitochondrial respiration, which was exacerbated in PD astrocytes containing a PARK2-variant. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166768 | GEO | 2021/02/16

REPOSITORIES: GEO

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Project description:Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granular layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, and this might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we permed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dctn2 interaction was shared across all PFF conditions, and Nckap1 and Ap3b2 were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

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Control (healthy) iPSC-derived astrocytes treated with: Media (control), TNFa 100ug/ml, Monomeric aSYN 10uM, or Fibril aSYN 10uM

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