State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neurology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, 361005, Fujian, China.
Shenzhen Research Institute of Xiamen University, Shenzhen, 518057, Guangdong, China.
Cerebellum. 2024 Dec;23(6):2575-2592. doi: 10.1007/s12311-024-01722-w. Epub 2024 Jul 25.
Polyglutamine spinocerebellar ataxias (polyQ SCAs) represent the most prevalent subtype of SCAs. The primary pathogenic mechanism is believed to be the gain-of-function neurotoxicity of polyQ proteins. Strategies such as enhancing the degradation or inhibiting the accumulation of these mutant proteins are pivotal for reducing their toxicity and slowing disease progression. The protein quality control (PQC) system, comprising primarily molecular chaperones and the ubiquitin‒proteasome system (UPS), is essential for maintaining protein homeostasis by regulating protein folding, trafficking, and degradation. Notably, polyQ proteins can disrupt the PQC system by sequestering its critical components and impairing its proteasomal functions. Therefore, restoring the PQC system through genetic or pharmacological interventions could potentially offer beneficial effects and alleviate the symptoms of the disease. Here, we will provide a review on the distribution, expression, and genetic or pharmacological intervention of protein quality control system in cellular or animal models of PolyQ SCAs.
多聚谷氨酰胺小脑共济失调（polyQ SCAs）是最常见的 SCA 亚型。主要的致病机制被认为是 polyQ 蛋白的获得性功能神经毒性。增强这些突变蛋白的降解或抑制其积累等策略对于降低其毒性和减缓疾病进展至关重要。蛋白质质量控制系统（PQC）主要由分子伴侣和泛素-蛋白酶体系统（UPS）组成，通过调节蛋白质折叠、运输和降解来维持蛋白质的内稳态。值得注意的是，polyQ 蛋白可以通过隔离其关键成分和损害其蛋白酶体功能来破坏 PQC 系统。因此，通过遗传或药理学干预来恢复 PQC 系统可能会产生有益的效果并减轻疾病的症状。在这里，我们将对 PQC 系统在 polyQ SCA 的细胞或动物模型中的分布、表达以及遗传或药理学干预进行综述。
