Proteostasis dysregulation in p.A53T-α-Synuclein iPSC-derived astrocytes exacerbates neurodegeneration in a Parkinson’s disease model with Lewy-like pathology

Abstract

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. The pathological effects of the p.A53T-αSyn mutation have been extensively investigated in neurons, yet the consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated induced pluripotent stem cells from PD patients carrying the p.A53T-αSyn mutation to astrocytes, which uncovered cell-intrinsic phenotypes, including calcium dyshomeostasis and accumulation of protein aggregates. Proteomic profiling and functional analyses revealed perturbed protein catabolic processes, involving the proteasome and autophagy, associated with lysosomal malfunction. Dopamine neurons co-cultured with p.A53T-αSyn astrocytes displayed exacerbated neurodegeneration with hallmark Lewy-like pathologies, reversed by control astrocytes at least due to their ability to resolve neuronal αSyn aggregates by endocytic clearance. Our findings underscore a critical impact of p.A53T-αSyn on astrocytic protein quality control mechanisms, positioning astrocytes as important contributors to PD neuropathology. Highlights iPSC-derived astrocytes from PD patients with the p.A53T-αSyn mutation display cell-autonomous pathological phenotypes and toxic αSyn accumulation Proteome and functional analyses reveal failure of major proteostasis mechanisms in p.A53T-αSyn astrocytes, largely related to lysosomal malfunction Inherent Lewy-like pathological features are identified in p.A53T-αSyn astrocyte-neuron co-cultures p.A53T-αSyn astrocytes induce PD-relevant neuropathology to healthy neurons Control but not p.A53T-αSyn astrocytes alleviate neuropathology in co-cultured neurons