Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport
Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport
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DOI：
10.1093/hmg/11.23.2837
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发表时间：
2002-11-01
影响因子：
3.5
通讯作者：
Miller, CCJ
中科院分区：
文献类型：
--
作者：
Brownlees, J;Ackerley, S;Miller, CCJ
Charcot-Marle-Tooth病（CMT）是周围神经系统最常见的遗传性疾病，神经丝的突变与某些形式的CMT有关。神经丝是神经元的主要中间纤维，但CMT突变诱导疾病的机制尚不清楚。在这里，我们证明了CMT突变的神经丝在培养的哺乳动物细胞和神经元中破坏了神经丝的组装和神经丝的轴突运输。我们还发现CMT突变的神经丝扰乱了神经元中线粒体的定位。神经纤维的积累是一些神经退行性疾病的病理特征，包括肌萎缩性侧索硬化症（ALS）、阿尔茨海默病、帕金森病、路易体痴呆和糖尿病性神经病。我们的研究结果表明，神经丝的异常组装和运输可以诱发神经系统疾病，并进一步暗示神经丝代谢缺陷与人类神经退行性疾病的发病机制有关。
Charcot-Marle-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, and mutations in neurofilaments have been linked to some forms of CMT. Neurofilaments are the major intermediate filaments of neurones, but the mechanisms by which the CMT mutations induce disease are not known. Here, we demonstrate that CMT mutant neurofilaments disrupt both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurones. We also show that CMT mutant neurofilaments perturb the localization of mitochondria in neurones. Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Our results demonstrate that aberrant neurofilament assembly and transport can induce neurological disease, and further implicate defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.