ATM-mediated co-chaperone DNAJB11 phosphorylation facilitates α-synuclein folding upon DNA double-stranded breaks

Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by the pathological accumulation of α-synuclein aggregates in dopaminergic neurons. This α-synuclein dyshomeostasis is caused by an interplay between aging, genetic and environmental factors. Aging process-related DNA damage and impaired DNA repair have recently been observed in the PD process. However, the precise neuronal response to DNA damage in PD remains largely unknown. Here, we demonstrate that double-strand breaks (DSBs) induce α-synuclein aggregation. Analysis of a large-scale proteomic analysis of ATM and ATR substrates identified a potential candidate in the HSP70 folding system responding to DNA damage. ATM phosphorylates co-chaperone DNAJB11 at threonine 188 which specifically facilitates the delivery of misfolded α-synuclein, but not tau or transthyretin protein, to the HSP70 folding system upon DSBs. Alteration of this response impairs the neurite outgrowth. Remarkably, DNAJB11 threonine 188 phosphorylation correlates with disease severity in transgenic SNCA mutant PD mice and PD patients. These findings reveal a DNA damage-responded HSP70 folding mechanism through a J-domain co-chaperone, offering a potential therapeutic target for PD.