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

Alpha-Synuclein (Syn) plays a central role in Parkinsons 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-Syn 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-Syn 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-Syn astrocytes displayed exacerbated neurodegeneration with hallmark Lewy-like pathologies, reversed by control astrocytes at least due to their ability to resolve neuronal Syn aggregates by endocytic clearance. Our findings underscore a critical impact of p.A53T-Syn on astrocytic protein quality control mechanisms, positioning astrocytes as important contributors to PD neuropathology. HighlightsO_LIiPSC-derived astrocytes from PD patients with the p.A53T-Syn mutation display cell-autonomous pathological phenotypes and toxic Syn accumulation C_LIO_LIProteome and functional analyses reveal failure of major proteostasis mechanisms in p.A53T-Syn astrocytes, largely related to lysosomal malfunction C_LIO_LIInherent Lewy-like pathological features are identified in p.A53T-Syn astrocyte-neuron co-cultures C_LIO_LIp.A53T-Syn astrocytes induce PD-relevant neuropathology to healthy neurons C_LIO_LIControl but not p.A53T-Syn astrocytes alleviate neuropathology in co-cultured neurons C_LI