Department of Medicine, University of Toronto, Toronto, Canada.
Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Canada.
Curr Neuropharmacol. 2021;19(7):1038-1068. doi: 10.2174/1570159X18666201116145507.
Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person's mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington's disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.
神经退行性疾病的特征是神经元的功能逐渐丧失和死亡，导致人的运动和/或认知能力逐渐受损。普遍假设蛋白质错误折叠和聚集导致神经毒性，并最终导致与这些疾病相关的神经元变性。新出现的实验证据以及最近的人类研究结果表明，热休克蛋白 70 相互作用蛋白 (CHIP) 的 C 末端或 STIP1 同源和 U -box 包含蛋白 1 (STUB1) 是一种参与神经退行性变的质量控制蛋白。在这里，我们回顾了 CHIP 与帕金森病、阿尔茨海默病、肌萎缩侧索硬化症和多聚谷氨酰胺疾病（包括亨廷顿病和脊髓小脑共济失调）发病机制中涉及的蛋白质相互作用并发挥作用的证据。我们还回顾了临床发现，鉴定出 STUB1 的突变是常染色体隐性和常染色体显性小脑共济失调的原因。我们提出，CHIP 调节可能具有治疗多种神经退行性疾病的潜力。
