Insertion of proteolipid protein into oligodendrocyte mitochondria regulates extracellular pH and adenosine triphosphate.
Insertion of proteolipid protein into oligodendrocyte mitochondria regulates extracellular pH and adenosine triphosphate.
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作者：
Appikatla S;Bessert D;Lee I;Hüttemann M;Mullins C;Somayajulu-Nitu M;Yao F;Skoff RP
蛋白脂质蛋白（PLP）和DM 20是最丰富的髓鞘蛋白，由人PLP 1和非人Plp 1蛋白脂质蛋白基因编码。PLP 1基因突变导致Pelizaeus-Merzbacher病（PMD），其中天然PLP 1基因的重复占PLP 1突变的70%。具有PLP 1复制的人类和具有额外PLP 1拷贝的小鼠具有广泛的神经元变性。导致神经元变性的机制尚不清楚。我们发现，当基因在小鼠和人类中复制时，天然PLP会进入线粒体。这份报告是PMD患者大脑中特定细胞缺陷的第一个证明;它验证了啮齿动物模型是研究PMD的理想模型。核编码的线粒体蛋白的插入需要特定的进口途径，我们表明，特定的半胱氨酸基序，Mia 40/Erv 1线粒体进口途径的一部分，存在于PLP，并需要其插入到线粒体。将天然PLP插入转染细胞的线粒体中会酸化培养基，部分原因是乳酸增加;它也会增加培养基中的ATP。同样的异常被发现在细胞外空间的小鼠大脑与额外拷贝的Plp 1。这些生理异常可以通过PLP半胱氨酸基序的突变来预防，这是Mia 40/Erv 1途径的标志。细胞外ATP增加和酸中毒导致神经元变性。我们的发现可能是Plp 1转基因小鼠中小胶质细胞被激活和促炎分子上调的机制。对这一代谢途径的调控可以恢复PMD患者的正常代谢，并为PMD患者提供治疗。
Proteolipid protein (PLP) and DM20, the most abundant myelin proteins, are coded by the human PLP1 and non-human Plp1 proteolipid protein gene. Mutations in the PLP1 gene cause Pelizaeus-Merzbacher Disease (PMD) with duplications of the native PLP1 gene accounting for 70% of PLP1 mutations. Humans with PLP1 duplications and mice with extra Plp1 copies have extensive neuronal degeneration. The mechanism that causes neuronal degeneration is unknown. We show that native PLP traffics to mitochondria when the gene is duplicated in mice and in humans. This report is the first demonstration of a specific cellular defect in brains of PMD patients; it validates rodent models as ideal models to study PMD. Insertion of nuclear-encoded mitochondrial proteins requires specific import pathways; we show that specific cysteine motifs, part of the Mia40/Erv1 mitochondrial import pathway, are present in PLP and are required for its insertion into mitochondria. Insertion of native PLP into mitochondria of transfected cells acidifies media, partially due to increased lactate; it also increases ATP in the media. The same abnormalities are found in the extracellular space of mouse brains with extra copies of Plp1. These physiological abnormalities are preventable by mutations in PLP cysteine motifs, a hallmark of the Mia40/Erv1 pathway. Increased extracellular ATP and acidosis lead to neuronal degeneration. Our findings may be the mechanism by which microglia are activated and pro-inflammatory molecules are up-regulated in Plp1 transgenic mice. Manipulation of this metabolic pathway may restore normal metabolism and provide therapy for PMD patients.