Mou Yongchao, Li Xue-Jun
Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford; Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
Neural Regen Res. 2019 Apr;14(4):574-577. doi: 10.4103/1673-5374.248108.
Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. Hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction. Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown. Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegia. This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.
轴突发育受损和变性是包括遗传性痉挛性截瘫在内的使人衰弱的神经退行性疾病的基础，遗传性痉挛性截瘫是一大类遗传性疾病。遗传性痉挛性截瘫是由长皮质脊髓束轴突的逆行变性引起的，导致腿部和臀部肌肉进行性痉挛和无力。它有70多种亚型，具有各种潜在的病理生理过程，如囊泡运输缺陷、脂质代谢、细胞器塑形、轴突运输和线粒体功能障碍。尽管遗传性痉挛性截瘫由具有不同病理特征的各种亚型组成，但线粒体形态和功能缺陷是遗传性痉挛性截瘫常见的细胞特征之一。线粒体形态和功能由几种关键的裂变和融合介质调节的线粒体动力学重塑。然而，线粒体动力学在遗传性痉挛性截瘫轴突缺陷中的作用仍 largely unknown。最近，研究报道了遗传性痉挛性截瘫神经元中线粒体形态紊乱。此外，无论是通过药理学还是遗传学方法下调线粒体裂变调节因子动力相关蛋白1，都可以挽救遗传性痉挛性截瘫神经元中的轴突生长缺陷，为治疗这些遗传性痉挛性截瘫提供了一个潜在的治疗靶点。这篇小型综述将描述线粒体裂变/融合的调节、线粒体动力学与轴突缺陷之间的联系，以及线粒体动力学在遗传性痉挛性截瘫轴突缺陷中的作用的最新进展。 （注：原文中“largely unknown”直译为“很大程度上未知”，这里意译为“仍不清楚”使表达更通顺；“mini-review”直译为“小型综述” ）
