Loss-of-function mutations in sorting nexin 14 (SNX14) cause autosomal recessive spinocerebellar ataxia 20, 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 high-energy-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.

中文翻译：

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SNX14 缺乏诱导的浦肯野细胞轴突线粒体转运缺陷是小脑共济失调的基础，并且可以通过丙戊酸盐逆转

排序连接蛋白 14 (SNX14) 中的功能丧失突变导致常染色体隐性遗传性脊髓小脑性共济失调 20，这是一种缺乏分子机制和小鼠模型的早发性小脑性共济失调。我们生成了 Snx14 缺陷小鼠模型并观察到严重的运动缺陷和细胞自主浦肯野细胞变性。SNX14 缺乏会破坏微管切断酶 spastin 的稳定性，从而破坏轴突中的微管组织和线粒体运输，这与显性遗传性痉挛性截瘫伴小脑共济失调有关，并损害轴突完整性和线粒体功能。轴突运输中断和线粒体功能障碍进一步导致高能量需求的浦肯野细胞退化，从而导致小脑共济失调的发病机制。抗癫痫药物丙戊酸盐通过恢复浦肯野细胞中的线粒体转运和功能改善了 Snx14 缺陷小鼠的运动缺陷和小脑退化。我们的研究揭示了 SNX14 依赖性轴突运输在小脑共济失调中的前所未有的作用，证明了 SNX14 和 spastin 在线粒体功能障碍中的融合，并建议丙戊酸盐作为潜在的治疗剂。