Defective pantothenate metabolism and neurodegeneration
Defective pantothenate metabolism and neurodegeneration
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DOI：
10.1042/bst20140098
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发表时间：
2014-08-01
影响因子：
3.9
通讯作者：
Hayflick, Susan J.
中科院分区：
文献类型：
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作者：
Hayflick, Susan J.
CoA（辅酶A）生物合成的先天性错误导致人类神经退行性疾病。PKAN（泛酸激酶相关神经变性）表现为脑、视网膜和睾丸损伤，由PANK2突变引起，PANK2是编码泛酸激酶线粒体形式的基因，是辅酶a合成的关键调节酶。最近发现编码辅酶a合成酶的基因突变导致类似的神经退行性疾病，这进一步引起了人们对这一途径的关注，并提出了一种共同的发病机制。CoA产生缺陷是如何导致神经退行性变的？为什么某些组织和细胞类型会选择性地脆弱？潜在的神经退行性过程是什么？其中一些问题的答案来自动物疾病模型，包括苍蝇和老鼠，以及直接来自人类。受损的组织类型共享可能导致其选择性脆弱性的关键特征。这些因素包括血液组织屏障的存在、氧化应激环境、组织代谢需求、这些组织中编码相似蛋白质的基因的相对表达以及细胞膜组成。自十多年前第一个基因发现以来，在理解这些重要的神经代谢疾病方面取得了实质性进展。随着PKAN的合理治疗方法的发展，我们预见到神经退行性变的预防，并希望神经再生或神经拯救。
Inborn errors of CoA (coenzyme A) biosynthesis lead to neurodegenerative disorders in humans. PKAN (pantothenate kinase-associated neurodegeneration) manifests with damage to brain, retina and testis and is caused by mutations in PANK2, the gene encoding the mitochondrial form of pantothenate kinase, a key regulatory enzyme in CoA synthesis. Further attention has been focused on this pathway by the recent discovery that mutations in the gene encoding CoA synthase lead to a similar neurodegenerative disorder, raising the spectre of a common mechanism of pathogenesis. How do defects in CoA production result in neurodegeneration? Why are certain tissues and cell types selectively vulnerable? And what is the underlying neurodegenerative process? Answers to some of these questions have come from animal models of disease, including flies and mice, as well as directly from humans. The damaged tissue types share key features that are likely to contribute to their selective vulnerability. These include the presence of a blood-tissue barrier, the milieu with respect to oxidative stress, tissue metabolic demand, relative expression of genes encoding similar proteins in these tissues and cell membrane composition. Substantial progress in understanding these important neurometabolic disorders has been made since the first gene discovery more than a decade ago. With rational therapeutics now in development for PKAN, we foresee prevention of neurodegeneration and hope for neuroregeneration or neuro-rescue.