GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria
GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria
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DOI：
10.1093/hmg/ddi121
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发表时间：
2005-04-15
影响因子：
3.5
通讯作者：
Palau, F
中科院分区：
文献类型：
--
作者：
Pedrola, L;Espert, A;Palau, F
神经节苷脂诱导的分化相关蛋白1基因GDAP1的突变可导致CMT 4A型，这是一种严重的常染色体隐性神经病变，与脱髓鞘或轴突表型相关。在这里，我们证明GDAP1在神经元中的表达远高于髓鞘雪旺细胞。我们通过在os -7细胞中与细胞器标记物的瞬时过表达和共定位，以及用抗GDAP1多克隆抗体对亚细胞组分进行western blot分析，研究了GDAP1在人神经母细胞瘤细胞系中的细胞定位。我们观察到GDAP1定位于线粒体。我们还表明，c端跨膜结构域对于线粒体的正确定位是必要的；然而，错义突变不会改变野生型蛋白的线粒体模式。我们的研究结果表明，CMT4A疾病实际上是一种主要累及轴突的线粒体神经病变，属于核基因突变引起的线粒体疾病的新类别。我们假设GDAP1可能与线粒体网络的维持有关。
Mutations in GDAP1, the ganglioside-induced differentiation-associated protein 1 gene, cause Charcot-Marie-Tooth (CMT) type 4A, a severe autosomal recessive form of neuropathy associated with either demyelinating or axonal phenotypes. Here, we demonstrate that GDAP1 has far greater expression in neurons than in myelinating Schwann cells. We investigated cell localization of GDAP1 in a human neuroblastoma cell line by means of transient overexpression and co-localization with organelle markers in COS-7 cells and by western blot analysis of subcell fractions with anti-GDAP1 polyclonal antibodies. We observed that GDAP1 is localized in mitochondria. We also show that C-terminal transmembrane domains are necessary for the correct localization in mitochondria; however, missense mutations do not change the mitochondrial pattern of the wild-type protein. Our findings suggest that CMT4A disease is in fact a mitochondrial neuropathy mainly involving axons and represents a disease belonging to the new category of mitochondrial disorders caused by mutations in nuclear genes. We postulate that GDAP1 may be related to the maintenance of the mitochondrial network.