Succinic acid treatment of SCA1 transgenic mice

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved behavior. Thus, treatment with succinic acid shows promise as a therapeutic adjuvant in neurodegenerative ataxias, and warrants further investigation. <b><br></b><b>All data from this manuscript will be made available upon acceptance by PLoS One.</b>

线粒体功能障碍在包括共济失调及其他运动障碍在内的神经退行性疾病中发挥关键作用，尤其好发于以小脑进行性退变为特征的此类疾病。本研究旨在探究线粒体氧化磷酸化（OXPHOS）缺陷在浦肯野细胞（Purkinje cell）驱动的1型脊髓小脑共济失调（SCA1）小鼠小脑组织中的作用。研究人员采用RNA测序转录组学、氧化磷酸化复合物组装分析及耗氧实验，发现携带突变型聚谷氨酰胺扩增的共济失调蛋白1的SCA1小鼠存在小脑氧化磷酸化复合物I（烟酰胺腺嘌呤二核苷酸-辅酶Q氧化还原酶）功能缺陷。复合物I的编码基因在症状发作期即出现上调，且该上调状态持续至疾病晚期；然而复合物I大分子的功能性组装受到削弱，经由复合物I的氧呼吸作用亦出现降低。对出现症状后的SCA1小鼠给予琥珀酸治疗——琥珀酸是一种可绕过复合物I功能缺陷的复合物II（琥珀酸脱氢酶）电子供体——可改善小鼠的小脑氧化磷酸化功能障碍，减轻小脑病理损伤并提升行为学表现。综上，琥珀酸治疗作为神经退行性共济失调的治疗佐剂具有良好应用前景，值得开展进一步研究。

本手稿的全部数据将在《公共科学图书馆·综合》（PLoS One）接收稿件后对外公开。