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

Abstract

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 H 2 O 2 -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.

Association of p53 with Neurodegeneration in Parkinson’s Disease

“…Chaperone and cochaperone systems are essential for protein folding or refolding and degradation of aggregated protein; thus, they prevent the cytotoxicity caused by aberrant protein accumulation [ 111 , 112 ]. p53 regulates the functional activity of HSP70 and HSP90 chaperone and cochaperone systems in neurodegenerative conditions [ 67 , 113 ]. Studies in PD cellular and animal models have shown that p53 activation increases the aggregation of α -synuclein in vulnerable neurons through inhibiting HSP70-mediated protein folding activity, accompanied by BAG5 protein overexpression [ 113 ].…”

“…p53 regulates the functional activity of HSP70 and HSP90 chaperone and cochaperone systems in neurodegenerative conditions [ 67 , 113 ]. Studies in PD cellular and animal models have shown that p53 activation increases the aggregation of α -synuclein in vulnerable neurons through inhibiting HSP70-mediated protein folding activity, accompanied by BAG5 protein overexpression [ 113 ]. BAG5 is an important stress-induced backup nucleotide exchange factor of HSP70 associated with the protein activation.…”

“…High levels of BAG5, however, inhibit the folding activity of the HSP70 chaperone, resulting in dysfunction of protein folding and refolding and subsequent abnormal protein aggregation. BAG5 expression is transcriptionally regulated by the p53 gene under stress conditions [ 113 ]. The gene silence of p53 causes a substantial decrease in BAG5 mRNA and protein levels in the stressed cells.…”

“…The gene silence of p53 causes a substantial decrease in BAG5 mRNA and protein levels in the stressed cells. Mechanism studies reveal that p53 can directly bind to the promoter and activate BAG5 transcription, leading to elevated levels of BAG5 under irreversible stress conditions [ 113 ]. p53 activation induces overexpression of BAG5 to inhibit the protein folding activity of HSP70, leading to the aggregation and accumulation of α -synuclein and subsequently cell toxicity and death.…”

Role of BAG5 in Protein Quality Control: Double-Edged Sword?

“…Astonishingly, some studies have reported that BAG5 interaction with other chaperones might interfere with their E3 ubiquitin ligase activity such that it might cause accumulation of toxic oligomers of α-synuclein (α-syn) ( Chen et al, 2020 ). Parkinson’s disease is a neurodegenerative disorder characterized by abnormal protein homeostasis causing accumulation of the protein α-syn in the form of Lewy bodies ( Orme et al, 2018 ; Goldman et al, 2020 ).…”