Title
FLZ Attenuates α-Synuclein-Induced Neurotoxicity by Activating Heat Shock Protein 70
Author
Xiu-Qi Bao, Xiao-Liang Wang, Dan Zhang
Year
2016
Journal
Molecular Neurobiology
Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. The pathology of PD is caused by progressive degeneration of dopaminergic neurons and is characterized by the presence of intracellular inclusions known as Lewy bodies, composed mainly of α-synuclein. Heat shock proteins (HSPs) are crucial in protein quality control in cells. HSP70 in particular prevents the aggregation of protein aggregation, such as α-synuclein, providing a degree of protection against PD. The compound FLZ has been shown to protect several PD models in previous studies and was reported as an HSP inducer to protect against MPP+-induced neurotoxicity, but the mechanism remains unclear. In this study, we investigated the effects of FLZ-mediated HSP70 induction in α-synuclein transgenic mice and cells. FLZ treatment alleviated motor dysfunction and improved dopaminergic neuronal function in α-synuclein transgenic mice. HSP70 protein expression and transcriptional activity were increased by FLZ treatment, eliciting a reduction of α-synuclein aggregation and associated toxicity. The inhibition of HSP70 by quercetin or HSP70 siRNA markedly attenuated the neuroprotective effects of FLZ, confirming that FLZ exerted a neuroprotective effect through HSP70. We revealed that FLZ directly bound to and increased the expression of Hip, a cochaperone of HSP70, which in turn enhanced HSP70 activity. In conclusion, we defined a critical role for HSP70 and its cochaperones activated by FLZ in preventing neurodegeneration and proposed that targeting the HSP70 system may represent a potential therapy for α-synuclein-related diseases, such as PD.
Instrument
J-815
Keywords
Circular dichroism, Protein folding, Aggregation, Biochemistry