Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease.
Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease.
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DOI：
10.1111/j.1582-4934.2007.00158.x
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发表时间：
2008-04
影响因子：
5.3
通讯作者：
Palau F
中科院分区：
文献类型：
--
作者：
Pedrola L;Espert A;Valdés-Sánchez T;Sánchez-Piris M;Sirkowski EE;Scherer SS;Fariñas I;Palau F
线粒体蛋白GDAP 1的突变是Charcot-Marie-Tooth 4A型疾病（CMT 4A）的原因，CMT 4A是与脱髓鞘、轴突或中间表型相关的严重形式的周围神经病变。GDAP 1定位于线粒体外膜，可能与线粒体网络动力学有关。我们有兴趣确定神经系统中的细胞表达和线粒体形态突变的影响以及疾病的发病机制。我们研究了GDAP 1在神经系统和背根神经节（DRG）神经元培养物中的表达。GDAP 1在脊髓的运动和感觉神经元以及其他大神经元如小脑浦肯野神经元、海马锥体神经元、嗅球的二尖瓣神经元和皮质锥体神经元中表达。在白色物质和神经根中缺乏GDAP 1染色表明胶质细胞不表达GDAP 1。在DRG培养物中，卫星细胞和雪旺细胞为GDAP 1阴性。GDAP 1诱导的线粒体碎片的过表达表明GDAP 1在线粒体动力学的裂变途径中的作用。错义突变表现出两种不同的模式：大多数突变诱导线粒体断裂，但T157 P突变表现出聚集模式。而GDAP 1的无效突变应该与蛋白质的功能丧失有关，错义突变可能通过不同的致病机制起作用，包括显性负效应，这表明不同的分子机制可能导致CMT 4A的发病机制。
Mutations in the mitochondrial protein GDAP1 are the cause of Charcot-Marie-Tooth type 4A disease (CMT4A), a severe form of peripheral neuropathy associated with either demyelinating, axonal or intermediate pheno-types. GDAP1 is located in the outer mitochondrial membrane and it seems that may be related with the mitochondrial network dynamics. We are interested to define cell expression in the nervous system and the effect of mutations in mitochondrial morphology and pathogenesis of the disease. We investigated GDAP1 expression in the nervous system and dorsal root ganglia (DRG) neuron cultures. GDAP1 is expressed in motor and sensory neurons of the spinal cord and other large neurons such as cerebellar Purkinje neurons, hippocampal pyramidal neurons, mitral neurons of the olfactory bulb and cortical pyramidal neurons. The lack of GDAP1 staining in the white matter and nerve roots suggested that glial cells do not express GDAP1. In DRG cultures satellite cells and Schwann cells were GDAP1-negative. Overexpression of GDAP1-induced fragmentation of mitochondria suggesting a role of GDAP1 in the fission pathway of the mitochondrial dynamics. Missense mutations showed two different patterns: most of them induced mitochondrial fragmentation but the T157P mutation showed an aggregation pattern. Whereas null mutations of GDAP1 should be associated with loss of function of the protein, missense mutations may act through different pathogenic mechanisms including a dominant-negative effect, suggesting that different molecular mechanisms may underlay the pathogenesis of CMT4A.
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影响因子：
4.4
作者：
BENOTHMANE, K;LOEB, D;VANCE, JM
通讯作者：
VANCE, JM
影响因子：
3.5
作者：
COMBARROS, O;CALLEJA, J;BERCIANO, J
通讯作者：
BERCIANO, J
影响因子：
3.5
作者：
Pedrola, L;Espert, A;Palau, F
通讯作者：
Palau, F
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作者：
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通讯作者：
Timmerman, V
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14.5
作者：
Sevilla, T;Cuesta, A;Vílchez, JJ
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Vílchez, JJ