title: FLZ Attenuates α-Synuclein-Induced Neurotoxicity by Activating Heat Shock Protein 70.
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.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.|State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing, 100050, China.
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Bao
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.|Beijing Institute for Brain Disorders, 10 Xitoutiao, Youanmen Wai, Beijing, 100054, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China. danzhang@imm.ac.cn.|State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing, 100050, China. danzhang@imm.ac.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D051844:alpha-Synuclein / Q000633:toxicity*
chemical_list: D044482:Benzeneacetamides; D018840:HSP70 Heat-Shock Proteins; D010636:Phenols; D051844:alpha-Synuclein; C084439:squamosamide
keywords: FLZ; HSP70-interacting protein; Heat shock protein 70; Parkinson’s disease; α-Synuclein