Hsp70在神经退行性疾病中的作用机制研究进展

Research progress on the mechanism of Hsp70 in neurodegenerative diseases

热休克蛋白Hsp70(heat shock protein 70,Hsp70)是一类广泛存在的分子伴侣。阿尔茨海默病(Alzheimer’s disease)、帕金森病(Parkinson’s disease)等神经退行性疾病共同的病理特征是错误折叠的蛋白质(包括Tau、α-突触核蛋白、TDP-43、朊蛋白和多聚谷氨酰胺蛋白)形成有毒性的寡聚体或淀粉样纤维。大量的研究表明,Hsp70可以调控这些蛋白质的代谢进程,包括将错误折叠的蛋白质重折叠、抑制蛋白质聚集以及降解错误折叠的蛋白质。Hsp70在发挥功能时需要相对应的辅助分子伴侣的帮助。该文详细论述了Hsp70抑制Tau蛋白病、α-突触核蛋白病、TDP-43蛋白病、传染性海绵状脑病以及多聚谷氨酰胺疾病的作用机制,重点阐述了Hsp70对神经退行性疾病中错误折叠蛋白质聚集和毒性的抑制作用,并讨论和展望了Hsp70在神经退行性疾病的治疗中存在的挑战和机遇。

Heat shock protein 70(Hsp70)is a ubiquitous molecular chaperone which plays important roles in a myriad of biological processes.Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are caused by the gradual loss of neuron structure and function.Their common pathological feature is toxic oligomers or amyloid aggregates formed by misfolded proteins including Tau,α-synuclein,TDP-43,prion protein,and polyglutamine protein.A large number of studies have shown that Hsp70 can regulate the metabolic processes of these proteins,including refolding of misfolded proteins,inhibiting protein aggregation,and degrading misfolded proteins and aggregates.Furthermore,co-chaperones can drive cellular functions of Hsp70.This review summarizes the role of Hsp70 in neurodegenerative diseases,elaborates the mechanism of Hsp70 inhibiting tauopathies,synucleinopathies,TDP-43 proteinopathies,transmissible spongiform encephalopathies,and polyglutamine diseases,and focuses on the suppression of Hsp70 on aggregation and toxicity of misfolded proteins in neurodegenerative diseases.Finally,we discuss and prospect the challenges and opportunities of Hsp70 in the treatment of neurodegenerative diseases.