Oxidative stress, cell cycle, and neurodegeneration

Abstract

While numerous studies have examined the existence of increased reactive oxygen species (ROS) in later-onset neurodegenerative disorders, the mechanism by which neurons die under conditions of oxidative stress remains largely unknown.Fairly recent evidence has suggested that one mechanism linked to the death of terminally differentiated neurons is aberrant reentry into the cell cycle.This phenomenon has been reported in Alzheimer disease (AD) patients (1), Down syndrome patients (2), and several mouse neurodegenerative models (3-5).We will discuss recent findings regarding the influence of oxidative stress on neurodegeneration and possible connections between oxidative stress and unscheduled cell cycle reentry, the understanding of which could lead to new strategies in the development of therapeutic agents for neurodegenerative disorders. Oxidative stress and neuron deathUnder normal physiological conditions, it is estimated that up to 1% of the mitochondrial electron flow leads to the formation of superoxide (O 2 •-), the primary oxygen free radical produced by mitochondria; and interference with electron transport can dramatically increase O 2 •-production.While these partially reduced oxygen species can attack iron sulfur centers in a variety of enzymes, O 2 •-is rapidly converted within the cell to hydrogen peroxide (H 2 O 2 ) by the superoxide dismutases (SOD1, SOD2, and SOD3).However, H 2 O 2 can react with reduced transition metals, via the Fenton reaction, to produce the highly reactive hydroxyl radical ( • OH), a far more damaging molecule to the cell.In addition to forming H 2 O 2 , O 2 •-radicals can rapidly react with nitric oxide (NO) to generate cytotoxic peroxynitrite anions (ONOO -).Peroxynitrite can react with carbon dioxide, leading to protein damage via the formation of nitrotyrosine and lipid oxidation.