Different proteolipid protein mutants exhibit unique metabolic defects
Different proteolipid protein mutants exhibit unique metabolic defects
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DOI：
10.1042/an20090028
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发表时间：
2009-01-01
期刊：
影响因子：
4.7
通讯作者：
Skoff, Robert P.
中科院分区：
文献类型：
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作者：
Huettemann, Maik;Zhang, Zhan;Skoff, Robert P.
PMD(Pelizaeus-Merzbacher病)是一种以寿命缩短和严重神经功能障碍为特征的中枢神经系统疾病，由PLP1(X连锁髓鞘蛋白脂蛋白)基因突变引起。大多数人类PLP1突变是由复制引起的；几乎所有其他突变都是由错义突变引起的。导致表型的细胞事件尚不清楚。在非人类中的相同突变使他们成为研究导致神经后遗症的机制的理想模型。在目前的研究中，我们发现Plp1重复(Plp1tg)的小鼠存在严重的线粒体缺陷，ATP减少50%，线粒体膜电位显著降低，线粒体数量增加。相比之下，携带Plp1错义突变的JP(Jimpy)小鼠表现出正常的线粒体功能。我们发现Plp1tg小鼠和Plp1转基因细胞中的PLP是以线粒体为靶点的。PLP具有允许插入线粒体的基序，其N端附近的缺失阻止了其与线粒体的共存。这些新数据表明，天然Plp1基因的Plp1错义突变和复制启动了独特的不同细胞反应。
PMD (Pelizaeus-Merzbacher disease), a CNS (central nervous system) disease characterized by shortened life-span and severe neural dysfunction, is caused by mutations of the PLP1 (X-linked myelin proteolipid protein) gene. The majority of human PLP1 mutations are caused by duplications; almost all others are caused by missense mutations. The cellular events leading to the phenotype are unknown. The same mutations in non-humans make them ideal models to study the mechanisms that cause neurological sequelae. In the present study we show that mice with Plp1 duplications (Plp1tg) have major mitochondrial deficits with a 50% reduction in ATP, a drastically reduced mitochondrial membrane potential and increased numbers of mitochondria. In contrast, the jp (jimpy) mouse with a Plp1 missense mutation exhibits normal mitochondrial function. We show that PLP in the Plp1tg mice and in Plp1-transfected cells is targeted to mitochondria. PLP has motifs permissive for insertion into mitochondria and deletions near its N-terminus prevent its co-localization to mitochondria. These novel data show that Plp1 missense mutations and duplications of the native Plp1 gene initiate uniquely different cellular responses.