The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.
The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.
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DOI：
10.1093/hmg/ddt319
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发表时间：
2013-12
影响因子：
3.5
通讯作者：
Wenzhang Wang;Li Li-Li;Wen‐lang Lin;D. Dickson;L. Petrucelli;Teng Zhang;Xinglong Wang
中科院分区：
文献类型：
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作者：
Wenzhang Wang;Li Li-Li;Wen‐lang Lin;D. Dickson;L. Petrucelli;Teng Zhang;Xinglong Wang
TDP-43突变可导致家族性ALS。越来越多的证据表明，线粒体动力学受损可能导致sod1相关ALS中运动神经元的选择性变性。在这项研究中，我们研究了TDP-43突变是否以及如何影响线粒体动力学和功能。我们证明，野生型TDP-43的过表达导致初级运动神经元神经突线粒体长度和密度减少，als相关的TDP-43突变体Q331K和M337V进一步加剧了这一特征。相反，抑制TDP-43导致神经突线粒体长度和密度显著增加，表明TDP-43在调节线粒体动力学方面具有特定作用。令人惊讶的是，TDP-43的过表达和抑制都损害了线粒体运动。我们进一步表明，细胞质中TDP-43的异常定位导致了大量和广泛的线粒体动力学异常。TDP-43在运动神经元中与线粒体共定位，ALS相关突变体增强了它们的共定位。重要的是，线粒体融合蛋白mitofusin 2 （Mfn2）的共表达可以消除TDP-43诱导的线粒体动力学异常和线粒体功能障碍。综上所述，这些数据表明突变体TDP-43通过增强线粒体定位来损害线粒体动力学，从而导致线粒体功能障碍。因此，线粒体动力学异常可能是ALS的共同特征，可能成为治疗ALS的潜在新靶点。
Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.