Protein Oxidation and Glycation in Neurodegenerative Diseases

The etiology of neuronal death in neurodegenerative diseases exemplified by Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) remains elusive. However, recent advances in molecular genetics and neurochemistry have tied neuronal death to excitotoxicity and oxidative damage, both of which can arise, at least in part, from defects in energy metabolism (1-3). While there is substantial evidence for progressive oxidative modification of proteins in normal aging (4), a great deal of recent research has focused on modification of the neuronal cytoskeleton via oxidative stress mechanisms as a key aspect of irreversible cellular dysfunction, ultimately leading to cell death (reviewed in Refs. 5 and 6). Under normal conditions, damage by oxygen radicals is kept in check by an efficient antioxidant cascade. However, in pathological conditions, the equilibrium between oxidants and antioxidants is likely altered, and there is good reason to think that the central nervous system is particularly vulnerable to oxidative stress due to the high rate of oxygen utilization and high content of unsaturated lipids.