Stress-induced p53 drives BAG5 cochaperone expression to control α-synuclein aggregation in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder with the pathological hallmark of α-synuclein aggregation. Dysregulation of α-synuclein homeostasis caused by aging, genetic, and environmental factors underlies the pathogenesis of PD. While chaperones are essential for proteostasis, whether modulation of cochaperones may participate in PD formation has not been fully characterized. Here, we assessed the expression of several HSP70- and HSP90-related factors under various stresses and found that BAG5 expression is distinctively elevated in etoposide- or H₂O₂-treated SH-SY5Y cells. Stress-induced p53 binds to the BAG5 promoter directly to stimulate BAG5. Induced BAG5 binds α-synuclein and HSP70 in both cell cultures and brain lysates from PD patients. Overexpressed BAG5 may result in the loss of its ability to promote HSP70. Importantly, α-synuclein aggregation in SH-SY5Y cells requires BAG5. BAG5 expression is also detected in transgenic SNCA mutant mice and in PD patients. Together, our data reveal stress-induced p53-BAG5-HSP70 regulation that provides a potential therapeutic angle for PD.