Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission.
Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission.
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DOI：
10.1016/j.drudis.2014.03.020
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发表时间：
2014-07
影响因子：
7.4
通讯作者：
Reddy, P. Hemachandra
中科院分区：
文献类型：
--
作者：
Reddy, P. Hemachandra
亨廷顿病（HD）是一种常染色体显性遗传的致死性、进行性神经退行性疾病，其特征在于舞蹈病、肢体不自主运动和认知障碍。自1993年发现HD基因以来，在利用HD的细胞和动物模型确定HD发病机制和进展以及开发和测试分子治疗靶点方面取得了巨大进展。最近的研究发现，突变亨廷顿蛋白（mHtt）与动力蛋白相关蛋白1（Drp1）相互作用，导致线粒体过度碎片化，导致HD影响神经元的线粒体动力学异常和神经元损伤。在开发可以减少过度线粒体分裂同时维持线粒体融合和分裂之间的正常平衡以及其中涉及过度线粒体分裂的疾病中的正常线粒体功能的分子方面已经取得了一些进展。在这篇文章中，我们强调的调查，确定参与过多的线粒体分裂在HD发病机制，并正在开发抑制剂的过度线粒体分裂的潜在治疗应用。
Huntington’s disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.
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