Brain atrophy and neuronal loss in alcoholism: a role for DNA damage?

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 vol umes. Neuropathological studies using unbiased stereological methods have p rovided evidence for loss of neurons in specific parts of the brain in chro nic alcoholics. The purpose of this paper is to propose a mechanism for thi s alcohol related neuronal loss. The hypothesis is based on the neurodegene ration observed in patients with the genetic disorder xeroderma pigmentosum (XP), who lack the capacity to carry out a specific type of DNA repair cal led nucleotide excision repair (NER). Some XP patients develop a progressiv e atrophic neurodegeneration, termed XP neurological disease, indicating th at endogenous DNA damage that is normally repaired by NER has the capacity to cause neuronal death. Accumulating evidence indicates that the neurodege nerative DNA damage that is responsible for neuronal loss in XP patients re sults from reactive oxygen species (ROS) and lipid peroxidation products, a nd has the capacity to inhibit gene expression by RNA polymerase II. Theref ore, the following model is proposed: chronic alcohol abuse results in incr eased levels of ROS and lipid peroxidation products in neurons, which resul ts in an overwhelming burden on the NER pathway, and increased steady state levels of DNA lesions that inhibit gene expression. This results in neuron al 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.