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. All data from this manuscript will be made available upon acceptance by PLoS One.

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，尤以小脑进行性退变为特征的此类疾病为甚。本研究旨在探究线粒体氧化磷酸化（oxidative phosphorylation, OXPHOS）功能缺陷在浦肯野细胞（Purkinje cell）介导的1型脊髓小脑共济失调（spinocerebellar ataxia type 1, SCA1）模型小鼠小脑组织中的作用。研究采用RNA测序转录组学、OXPHOS复合物组装分析及耗氧量检测实验，结果显示：携带突变型聚谷氨酰胺扩增共济失调蛋白1的SCA1模型小鼠，其小脑的OXPHOS复合物I（NADH-辅酶Q氧化还原酶）存在功能缺陷。复合物I的编码基因在症状发作初期即出现上调，且该上调状态可持续至疾病晚期；但复合物I大分子的功能性组装受到削弱，经复合物I的氧呼吸速率亦显著降低。对症状出现后的SCA1模型小鼠给予琥珀酸治疗——琥珀酸作为复合物II（琥珀酸脱氢酶）的电子供体，可绕过复合物I的功能缺陷——能够有效改善其小脑OXPHOS功能异常、减轻病理损伤并优化行为表现。综上，琥珀酸作为治疗佐剂在神经退行性共济失调中具有应用前景，值得进一步深入研究。本文所有数据将在《PLoS ONE》接收该稿后公开。