Ubiquinone (Coenzyme Q10) and Mitochondria in Oxidative Stress of Parkinson’s Disease
Ubiquinone (Coenzyme Q10) and Mitochondria in Oxidative Stress of Parkinson’s Disease
复制标题
DOI：
10.1159/000046889
复制
发表时间：
2001-05
期刊：
影响因子：
--
通讯作者：
Manuchair Ebadi;P. Govitrapong;Sunita Sharma;D. Muralikrishnan;S. Shavali;Pellett Lj;R. Schafer;C. B. Albano;J. Eken
中科院分区：
文献类型：
--
作者：
Manuchair Ebadi;P. Govitrapong;Sunita Sharma;D. Muralikrishnan;S. Shavali;Pellett Lj;R. Schafer;C. B. Albano;J. Eken
帕金森氏病是仅次于阿尔茨海默病的第二大常见神经退行性疾病，约有1%的50岁以上人群受到影响。由于人口老龄化，世界范围内的疾病流行呈上升趋势。帕金森病的明确神经病理学诊断要求黑质和相关脑干核团中的多巴胺能神经元丢失，剩余神经细胞中存在路易小体。遗传因素在帕金森氏病发病机制中的作用日益被人们所认识。最近，在更常见的散发性或特发性帕金森病中，在4号染色体上的α-突触核蛋白基因中发现了足以导致罕见的常染色体显性遗传形式的帕金森病的点突变，并在生化水平上证实了线粒体呼吸链复合体I的缺陷。帕金森病黑质的疾病特异性缺陷已被证实。这些发现以及观察到导致人类帕金森样综合征的神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)通过抑制复合体I发挥作用，引发了人们对帕金森病线粒体遗传学的研究兴趣。氧化磷酸化由位于线粒体内膜的五种蛋白质-脂酶复合体组成，其中含有黄素(FMN、FAD)、奎宁类化合物(辅酶Q10、辅酶Q10)和过渡金属化合物(铁-硫簇、血红素、蛋白结合铜)。这些酶被命名为复合体I(NADH：泛醌氧化还原酶，EC 1.6。络合物II(琥珀酸：泛醌氧化还原酶，EC 1.3.5.1)，络合物III(泛喹酚：细胞色素铁氧化还原酶，EC 1.10.2.2)，络合物IV(铁细胞色素c：氧氧化还原酶或细胞色素C氧化酶，EC 1.9.3.1)，以及络合物V(三磷酸腺苷合成酶，EC 3.6.1.34)。帕金森氏病患者纹状体内线粒体氧化磷酸化缺陷，表现为NADH辅酶Q还原酶(复合体I)活性降低。复合体I的活性降低出现在黑质，但不存在于大脑的其他区域，如苍白球或大脑皮层。因此，线粒体损伤的特异性可能在黑质纹状体多巴胺能神经元变性中起一定作用。MPTP产生1-甲基-4-苯基吡啶(MPP+)破坏黑质中的多巴胺能神经元的事实支持了这一观点。虽然帕金森病患者血清辅酶Q10水平正常，但辅酶Q10能够减轻MPTP诱导的纹状体多巴胺能神经元的丢失。
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson’s disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson’s disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the α-synuclein gene on chromosome 4 in the much more common sporadic, or ‘idiopathic’ form of Parkinson’s disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson’s disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson’s disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP+) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson’s disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.