Dafinca Ruxandra, Tosat-Bitrian Carlota, Carroll Emily, Vahsen Björn F, Gilbert-Jaramillo Javier, Scaber Jakub, Feneberg Emily, Johnson Errin, Talbot Kevin
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
Kavli Institute for Nanoscience Discovery, Oxford OX1 3QU, UK.
Brain Commun. 2024 Oct 5;6(5):fcae350. doi: 10.1093/braincomms/fcae350. eCollection 2024.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43 mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43 with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.
肌萎缩侧索硬化症（ALS）是一种运动系统的神经退行性疾病，其决定因素复杂，包括遗传和非遗传因素。ALS的一个关键病理特征是受影响的运动神经元中TDP - 43在细胞质中的定位错误和聚集，97%的病例中都有发现。最近的报告表明，线粒体功能障碍在ALS的运动神经元变性中起重要作用，并且TDP - 43调节多种线粒体转录本。在本研究中，我们使用来自携带TDP - 43突变的ALS患者的诱导多能干细胞衍生的运动神经元和转基因TDP - 43小鼠模型，以确定TDP - 43突变如何改变线粒体功能和轴突运输。我们检测到患者诱导多能干细胞衍生的运动神经元中线粒体呼吸和ATP产生显著降低，这与TDP - 43与ATPB和COX5A之间的相互作用有关。在患者诱导多能干细胞衍生的运动神经元中检测到逆行轴突运输速度的下游降低，这与运动蛋白复合物DCTN1/动力蛋白的下调相关。在患者诱导多能干细胞衍生的运动神经元中过表达DCTN1显著增加了逆行移动线粒体的百分比并降低了静止线粒体的百分比。这项研究表明，携带TDP - 43突变的ALS诱导多能干细胞衍生的运动神经元在基本线粒体功能方面存在缺陷，对逆行轴突运输有下游影响，而过表达DCTN1可部分挽救这种情况。
