Compartment specific mitochondrial dysfunction in Drosophila knock-in model of ALS reversed by altered gene expression of OXPHOS subunits and pro-fission factor Drp1.
Compartment specific mitochondrial dysfunction in Drosophila knock-in model of ALS reversed by altered gene expression of OXPHOS subunits and pro-fission factor Drp1.
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DOI：
10.1016/j.mcn.2023.103834
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发表时间：
2023-06
期刊：
影响因子：
--
通讯作者：
Wharton KA
中科院分区：
文献类型：
--
作者：
Nemtsova Y;Steinert BL;Wharton KA
肌萎缩性侧索硬化症（ALS）是一种致命的多系统神经退行性疾病，以运动功能丧失为特征。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）和融合肉瘤（FUS），到维持细胞氧化还原稳态的基因，如超氧化物歧化酶1 （SOD1）。尽管在遗传起源和特定的细胞缺陷方面各不相同，但ALS病例之间存在致病和临床共性。线粒体缺陷就是这样一种常见的病理，它被认为是在症状发作之前发生的，而不是症状发作的结果，这使得这些细胞器成为多种神经退行性疾病（包括ALS）的有希望的治疗靶点。根据神经元在整个生命过程中的稳态需要，线粒体通常穿梭于不同的亚细胞区室，调节代谢物和能量产生、脂质代谢、缓冲钙，以及影响其他必要的细胞过程。虽然最初被认为是一种基于运动功能急剧丧失和运动神经元细胞死亡的运动神经元疾病，但对ALS的研究表明，非运动神经元和神经胶质细胞都存在分子和细胞缺陷，通常在运动神经元死亡之前，这表明这些细胞类型的破坏可能启动和/或促进运动神经元功能的下降。在这里，我们研究了ALS果蝇Sod1敲入模型中的线粒体。在体内，深入研究发现先天性线粒体功能障碍在运动症状出现之前就很明显，病变感觉神经元中线粒体的亚细胞分布异常，轴突运输机制没有明显缺陷。在完整的运动回路中使用基因表达的生物传感器，感觉神经元线粒体形态、氧化磷酸化和线粒体自噬的变化与运动减少相关。我们证明了特定电子传递链（ETC）亚基的靶向表达可以减轻als相关的线粒体形态和功能缺陷。
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 the redox homeostasis of the cell, like superoxide dismutase 1 (SOD1). Although varied in genetic origin and in specific cellular defects, there are pathogenic and clinical commonalities between cases of ALS. Defects in mitochondria is one such common pathology, which is thought to occur prior to, rather than as a consequence of symptom onset, making these organelles a promising therapeutic target for multiple neurodegenerative diseases, including ALS. Depending on the homeostatic needs of neurons throughout life, mitochondria are normally shuttled to different subcellular compartments regulating metabolite and energy production, lipid metabolism, and buffering calcium, as well as influencing other essential cellular processes. While initially considered a motor-neuron disease based on the dramatic loss in motor function and motor neuron cell death, studies of ALS have shown molecular and cellular defects in non-motor neurons and glial cells alike, often preceding motor neuron death, suggesting that a disruption in these cell types could initiate and/or facilitate a decline in motor neuron function. Here, we investigate mitochondria in a Drosophila Sod1 knock-in model of ALS. In depth, in vivo, examination reveals innate mitochondrial dysfunction evident prior to motor-symptom onset, with abnormal subcellular distributions of mitochondria in diseased sensory neurons with no apparent defects in the axonal transport machinery. Using genetically expressed biosensors in the context of the intact motor circuit, changes in mitochondrial morphology, oxidative phosphorylation, and mitophagy in sensory neurons are correlated with a reduction in locomotion. We demonstrate that targeted expression of specific electron transport chain (ETC) subunits can alleviate ALS-associated defects in mitochondrial morphology and function.
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