Proceedings of the National Academy of Sciences of the United States of AmericaNov 17, 2025

Faulty protein balance in mutant α-synuclein support cells worsens Parkinson’s-like brain damage in a stem cell model

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Updated Jan 7, 2026

Abstract

The p.A53T mutation of Alpha-Synuclein is associated with significant cellular dysfunction in astrocytes derived from patients with early-onset Parkinson's disease.

Astrocytes with the p.A53T mutation exhibited calcium imbalances and accumulated protein aggregates, including phosphorylated Alpha-Synuclein.
Proteomic analysis revealed disrupted protein breakdown processes and impaired lysosomal function in p.A53T-αSyn astrocytes.
The endocytic clearance capacity of p.A53T-αSyn astrocytes was reduced, affecting their ability to manage external Alpha-Synuclein.
Dopamine neurons cultured with p.A53T-αSyn astrocytes showed Lewy-like pathologies and increased neurodegeneration, resembling changes seen in Parkinson’s disease brains.
Control astrocytes provided a neuroprotective effect, reducing the pathologies caused by p.A53T-αSyn astrocytes.
The findings suggest that astrocytes play a significant role in the neuropathology of Parkinson's disease.

Simplified

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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Faulty protein balance in mutant α-synuclein support cells worsens Parkinson’s-like brain damage in a stem cell model

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