Mechanisms of Neuronal Apoptosis In Vivo

摘要

Neuronal cell death in the central nervous system (CNS) has broad significance for military personnel in combat and veteran status and civilians. Neuronal cell death in the form of apoptosis or necrosis occurs after exposure to neurotoxins, chemical warfare agents, radiation, viruses, and after seizures, trauma, limb amputation, and hypoxic-ischemia caused by cardiac arrest, stroke, asphyxiation, and increased intracranial pressure. Secondary brain damage can result from hemorrhagic and hypovolemic shock. The goal of this project was to identify mechanisms of neuronal cell death. We discovered that injury-induced neuronal apoptosis in the adult CNS requires the Bax gene and involves an upregulation of Bax and its translocation to mitochondria. The Bax upregulation requires a functional p53 gene. The early events of target deprivation/axotomy- induced neuronal apoptosis involves oxidative stress, DNA damage, p53 phosphorylation, and subcellular redistribution of death proteins. The process of neuronal apoptosis involves a perinuclear accumulation of mitochondria and cytochrome C release from mitochondria and caspase-3 activation. Upstream signals for neuronal apoptosis within the CNS involve the accumulation of specific forms of DNA lesions, including single-strand breaks, that trigger p53 activation and downstream cell death. The DNA damage that occurs early during neuronal apoptosis has a reactive oxygen species fingerprint.