Altered neuronal mitochondrial coenzyme a synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2
Altered neuronal mitochondrial coenzyme a synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2
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DOI：
10.1523/jneurosci.4265-04.2005
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发表时间：
2005-01-19
影响因子：
5.3
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Kotzbauer, PT;Truax, AC;Lee, VMY
已经在具有脑铁积聚的神经变性（NBIA;以前为Hallervorden-Spatz病）的患者中鉴定出泛酸激酶2（PANK 2）基因的突变。然而，这些突变导致神经变性的机制尚不清楚，特别是考虑到人类中存在多个泛酸激酶基因和多个具有潜在不同亚细胞定位的PanK 2转录本。我们证明PanK 2蛋白定位于人脑神经元的线粒体，将其与其他不具有神经靶向序列的泛酸激酶区分开来。从最5 5'起始位点翻译的PanK 2蛋白在两个位点被线粒体加工肽酶连续切割，产生与人脑提取物中发现的相同的长寿命48 kDa成熟蛋白。成熟蛋白催化辅酶A（CoA）合成的初始步骤，但对酰基CoA的种类而不是CoA本身显示反馈抑制。一些，但不是所有的疾病相关的点突变导致催化活性显着降低。最常见的突变G521 R导致中间PanK 2亚型的显著不稳定性和成熟亚型的产量减少。这些结果表明NBIA是由破坏PanK 2蛋白水平和催化活性的突变引起的神经元线粒体脂质代谢改变引起的。
Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden - Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5 5' start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.