Molecular Biology, Cell Biology, and Biochemistry Department, Brown University, Providence, RI 02912, United States.
Molecular Biology, Cell Biology, and Biochemistry Department, Brown University, Providence, RI 02912, United States; Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI 02912, United States.
Mol Cell Neurosci. 2023 Jun;125:103834. doi: 10.1016/j.mcn.2023.103834. Epub 2023 Mar 1.
Amyotrophic Lateral Sclerosis (ALS) is a fatal multisystem neurodegenerative disease, characterized by a loss in motor function. ALS is genetically diverse, with mutations in genes ranging from those regulating RNA metabolism, like TAR DNA-binding protein (TDP-43) and Fused in sarcoma (FUS), to those that act to maintain cellular redox homeostasis, like superoxide dismutase 1 (SOD1). Although varied in genetic origin, pathogenic and clinical commonalities are clearly evident between cases of ALS. Defects in mitochondria is one such common pathology, thought to occur prior to, rather than as a consequence of symptom onset, making these organelles a promising therapeutic target for ALS, as well as other neurodegenerative diseases. Depending on the homeostatic needs of neurons throughout life, mitochondria are normally shuttled to different subcellular compartments to regulate metabolite and energy production, lipid metabolism, and buffer calcium. While originally considered a motor neuron disease due to the dramatic loss in motor function accompanied by motor neuron cell death in ALS patients, many studies have now implicated non-motor neurons and glial cells alike. Defects in non-motor neuron cell types often preceed motor neuron death suggesting their dysfunction may initiate and/or facilitate the decline in motor neuron health. Here, we investigate mitochondria in a Drosophila Sod1 knock-in model of ALS. In depth, in vivo, examination reveals mitochondrial dysfunction evident prior to onset of motor neuron degeneration. Genetically encoded redox biosensors identify a general disruption in the electron transport chain (ETC). Compartment specific abnormalities in mitochondrial morphology is observed in diseased sensory neurons, accompanied by no apparent defects in the axonal transport machinery, but instead an increase in mitophagy in synaptic regions. The decrease in networked mitochondria at the synapse is reversed upon downregulation of the pro-fission factor Drp1. Furthermore, altered expression of specific OXPHOS subunits reverses ALS-associated defects in mitochondrial morphology and function.
肌萎缩侧索硬化症（ALS）是一种致命的多系统神经退行性疾病，其特征是运动功能丧失。ALS 具有遗传多样性，突变基因范围从调节 RNA 代谢的基因（如 TAR DNA 结合蛋白（TDP-43）和 Fused in sarcoma（FUS））到那些维持细胞氧化还原平衡的基因（如超氧化物歧化酶 1（SOD1））。尽管遗传起源不同，但 ALS 病例之间存在明显的致病性和临床共性。线粒体缺陷是一种常见的病理学，据认为这种缺陷发生在症状出现之前，而不是之后，这使得这些细胞器成为 ALS 以及其他神经退行性疾病的有前途的治疗靶点。根据神经元在整个生命过程中的稳态需求，线粒体通常被转运到不同的亚细胞区室，以调节代谢物和能量产生、脂质代谢和缓冲钙。虽然最初由于 ALS 患者运动功能的急剧丧失和运动神经元细胞死亡而被认为是一种运动神经元疾病，但许多研究现在已经牵连到非运动神经元和神经胶质细胞。非运动神经元细胞类型的缺陷通常先于运动神经元死亡，这表明它们的功能障碍可能引发和/或促进运动神经元健康的下降。在这里，我们在果蝇 Sod1 敲入 ALS 模型中研究了线粒体。深入的体内检查显示，线粒体功能障碍在运动神经元退化之前就已经出现。遗传编码的氧化还原生物传感器识别到电子传递链（ETC）的普遍中断。在患病的感觉神经元中观察到线粒体形态的特定区室异常，同时轴突运输机制没有明显缺陷，但在突触区域出现了更多的线粒体自噬。突触处网络状线粒体的减少在下调促分裂因子 Drp1 后得到逆转。此外，特定 OXPHOS 亚基的改变表达逆转了与 ALS 相关的线粒体形态和功能缺陷。
