Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy.
Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy.
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DOI：
10.1242/dmm.021766
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发表时间：
2016-01
影响因子：
4.3
通讯作者：
Li XJ
中科院分区：
文献类型：
--
作者：
Xu CC;Denton KR;Wang ZB;Zhang X;Li XJ
脊髓性肌萎缩症(SMA)是由运动神经元存活的端粒(SMN1)基因突变和随后的功能性SMN水平降低引起的，其特征是脊髓运动神经元的特异性变性。SMN是一种普遍表达的蛋白质，它的缺失如何导致受SMA影响的个体的脊髓运动神经元特异性变性尚不清楚。在这项研究中，我们通过产生SMA 1型患者特异性诱导的多能干细胞(IPSCs)并将其分化为脊髓运动神经元，研究了SMN在人类运动神经元线粒体轴突运输和形态中的作用。脊髓运动神经元的初始规格没有受到影响，但这些SMA脊髓运动神经元经过长期培养后特别退化。此外，在SMA脊髓运动神经元的早期阶段，轴突的线粒体数量、线粒体面积和线粒体转运显著减少，而在SMA前脑神经元中则没有。SMN表达下调会导致人胚胎干细胞来源的脊髓运动神经元出现类似的线粒体缺陷，证实SMN缺陷会导致线粒体动力学受损。最后，N-乙酰半胱氨酸(NAC)的应用减轻了SMA长期培养中线粒体运输和形态的损害，并挽救了运动神经元的变性。此外，NAC还能改善SMA脊髓运动神经元线粒体膜电位的降低，提示NAC可能通过改善线粒体健康来挽救细胞凋亡和运动神经元变性。总体而言，我们的数据表明，SMN缺乏导致线粒体运输和形态异常以及随后线粒体健康状况的降低，这与SMA脊髓运动神经元的特异性退化有关。摘要：本研究首次在人类脊髓性肌萎缩症模型中提供了线粒体动力学受损的证据，为这种毁灭性疾病提供了潜在的治疗靶点。
Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA. Summary: This study provides the first evidence in human models of spinal muscular atrophy of impaired mitochondrial dynamics, which serve as potential therapeutic targets for this devastating disease.