Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases.
Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases.
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DOI：
10.3390/ph3040839
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Martin LJ
中科院分区：
文献类型：
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作者：
Martin LJ
阿尔茨海默病（AD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）是人类最常见的成人神经退行性疾病。它们的特点是选择性脆弱的神经系统中存在明显的与年龄相关的神经变性。某些形式的 AD、PD 和 ALS 是遗传性的，导致这些疾病的基因已被识别。然而，神经元细胞死亡的机制尚未解决。形态学、生化、遗传以及细胞和动物模型研究表明，线粒体可能在这种神经变性中发挥作用。根据细胞死亡矩阵理论，线粒体的功能和特性可能使选择性脆弱神经元的子集本质上容易受到细胞衰老和压力以及叠加的遗传变异的影响，从而引发神经退行性变。在 AD 中，参与氧化磷酸化、氧化损伤以及 Aβ 和淀粉样前体蛋白线粒体结合的酶发生了变化。在帕金森病中，假定的线粒体蛋白发生突变，并且在黑质神经元中发现了线粒体 DNA 突变。在 ALS 中，线粒体呼吸链酶和线粒体细胞死亡蛋白发生变化。人类神经退行性疾病的转基因小鼠模型开始揭示涉及线粒体和线粒体通透性转换孔的选择性神经元脆弱性生物学的可能原理。这篇综述总结了线粒体病理学如何导致 AD、PD 和 ALS 中的神经元死亡，并可以作为药物治疗的目标。
Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.