ArticleProceedings of the National Academy of Sciences of the United States of America2025
Dysregulated proteostasis in p.A53T-α-Synuclein astrocytes aggravates Lewy-like neuropathology in a Parkinson's disease iPSC model.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed.
- Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.Neurotoxicity research · 2026Review
- Review
Corrections and comments
- Erratum issued
Authors and funding
16 authors.
Funding
Abstract
Alpha-Synuclein (αSyn) plays a central role in Parkinson's disease (PD), and the p.A53T mutation causes an early-onset familial form of PD with severe manifestations. While its effects on neurons are well studied, its consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated patient-derived p.A53T-αSyn induced pluripotent stem cells (iPSC) to ventral midbrain astrocytes and characterized them via comprehensive molecular, functional, and proteomic analyses. Gene-corrected and healthy iPSC-derived astrocytes served as controls. To assess the effects of p.A53T-αSyn astrocytes on dopamine neurons, we established neuron-astrocyte cocultures of iPSC-derived control and mutant cells at all combinations. Our analyses uncovered cell-intrinsic pathologies in p.A53T-αSyn astrocytes, such as calcium dyshomeostasis, and accumulation of protein aggregates including those of phosphorylated αSyn. Proteomic and mechanistic studies demonstrated perturbed protein catabolic processes, with associated disturbances in lysosomal function and mTOR signaling. These deficits reduced the endocytic clearance capacity of p.A53T-αSyn astrocytes and their ability to process exogenous αSyn cargo. p.A53T-αSyn dopamine neurons cocultured with p.A53T-αSyn astrocytes displayed Lewy-like pathologies, mirroring the histopathological hallmarks identified in postmortem PD brains and exacerbated neurodegeneration, in anatomical and functional aspects. Control astrocytes mitigated these pathologies, highlighting their neuroprotective role. Additionally, p.A53T-αSyn astrocytes induced PD-relevant pathology ιn control neurons. Our findings, validated using an isogenic pair, demonstrate a critical impact of p.A53T-αSyn in disrupting astrocytic protein quality control mechanisms and establish astrocytes as active contributors to PD neuropathology. Our two-dimensional coculture model reflects key aspects of PD pathology, offering a relevant platform for mechanistic and drug discovery studies.
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