Brain atrophy and neuronal loss in alcoholism: a role for DNA damage?
Brain atrophy and neuronal loss in alcoholism: a role for DNA damage?
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DOI：
10.1016/s0197-0186(00)00051-6
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发表时间：
2000-11-01
影响因子：
4.2
通讯作者：
Brooks, PJ
中科院分区：
文献类型：
--
作者：
Brooks, PJ
慢性酗酒对身体的多个器官包括大脑都有有害影响。神经放射学研究表明，慢性酗酒者的大脑灰质和白质体积都会减少。使用无偏立体学方法的神经病理学研究为慢性酗酒者大脑特定部位的神经元缺失提供了证据。本文的目的是提出一种与酒精相关的神经元缺失的机制。该假说基于在患有遗传性疾病——着色性干皮病（XP）的患者中观察到的神经退行性变，这些患者缺乏进行一种称为核苷酸切除修复（NER）的特定类型DNA修复的能力。一些XP患者会发展为进行性萎缩性神经退行性变，称为XP神经系统疾病，这表明通常由NER修复的内源性DNA损伤有导致神经元死亡的能力。越来越多的证据表明，导致XP患者神经元缺失的神经退行性DNA损伤是由活性氧物质（ROS）和脂质过氧化产物引起的，并且有抑制RNA聚合酶II基因表达的能力。因此，提出以下模型：慢性酗酒导致神经元中ROS和脂质过氧化产物水平升高，这给NER通路带来巨大负担，并使抑制基因表达的DNA损伤的稳态水平升高。这要么通过必需基因产物水平的降低，要么通过细胞凋亡导致神经元死亡。讨论了该模型对未来研究的意义。（C）2000爱思唯尔科学有限公司。保留所有权利。
Chronic alcohol abuse has deleterious effects on several organs in the body including the brain. Neuroradiological studies have demonstrated that the brains of chronic alcoholics undergo loss of both gray and white matter volumes. Neuropathological studies using unbiased stereological methods have provided evidence for loss of neurons in specific parts of the brain in chronic alcoholics. The purpose of this paper is to propose a mechanism for this alcohol related neuronal loss. The hypothesis is based on the neurodegeneration observed in patients with the genetic disorder xeroderma pigmentosum (XP), who lack the capacity to carry out a specific type of DNA repair called nucleotide excision repair (NER). Some XP patients develop a progressive atrophic neurodegeneration, termed XP neurological disease, indicating that endogenous DNA damage that is normally repaired by NER has the capacity to cause neuronal death. Accumulating evidence indicates that the neurodegenerative DNA damage that is responsible for neuronal loss in XP patients results from reactive oxygen species (ROS) and lipid peroxidation products, and has the capacity to inhibit gene expression by RNA polymerase II. Therefore, the following model is proposed: chronic alcohol abuse results in increased levels of ROS and lipid peroxidation products in neurons, which results in an overwhelming burden on the NER pathway, and increased steady state levels of DNA lesions that inhibit gene expression. This results in neuronal death either by reduction in the levels of essential gene products or by apoptosis. The implications of this model for future studies are discussed. (C) 2000 Elsevier Science Ltd. All rights reserved.