SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate

作     者：Hongfeng Zhang Yujuan Hong Weijie Yang Ruimin Wang Ting Yao Jian Wang Ke Liu Huilong Yuan Chaoqun Xu Yuanyuan Zhou Guanxian Li Lishan Zhang Hong Luo Xian Zhang Dan Du Hao Sun Qiuyang Zheng Yun-Wu Zhang Yingjun Zhao Ying Zhou Huaxi Xu Xin Wang Hongfeng Zhang;Yujuan Hong;Weijie Yang;Ruimin Wang;Ting Yao;Jian Wang;Ke Liu;Huilong Yuan;Chaoqun Xu;Yuanyuan Zhou;Guanxian Li;Lishan Zhang;Hong Luo;Xian Zhang;Dan Du;Hao Sun;Qiuyang Zheng;Yun-Wu Zhang;Yingjun Zhao;Ying Zhou;Huaxi Xu;Xin Wang

作者机构：State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience School of Medicine Xiamen University National Institute for Data Science in Health and Medicine School of Medicine Xiamen University Cancer Research Center Department of Stomatology School of Medicine Xiamen University 

出 版 物：《National Science Review》 (国家科学评论(英文版))

年 卷 期：2021年第8卷第7期

页      面：72-85页

核心收录：

学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：supported in part by the National Natural Science Foundation of China (81822014, 31871077 and 81571176 to X.W., 81701349 to H.Z., 81802823 to Ying Z.) the National Key R&D Program of China (2016YFC1305900 to X.W.) the Natural Science Foundation of Fujian Province of China(2017J06021 to X.W., 2018J01054 to Ying Z.) the Fundamental Research Funds for the Chinese Central Universities(20720150061 to X.W.) 

主　　题：sorting nexin 14 cerebellar ataxia Purkinje cell degeneration mitochondrial dysfunction axonal transport valproate 

摘      要：Loss-of-function mutations in sorting nexin 14(SNX14) cause autosomal recessive spinocerebellar ataxia20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of highenergy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggested valproate as a potential therapeutic agent.