DO DEFECTS IN MITOCHONDRIAL ENERGY-METABOLISM UNDERLIE THE PATHOLOGY OF NEURODEGENERATIVE DISEASES

The pathogenesis of nerve cell death in neurodegenerative diseases is unknown. An attractive hypothesis is that an impairment of energy metabolism may underlie slow excitotoxic neuronal death, Several studies have demonstrated mitochondrial or oxidative defects in neurodegenerative diseases impaired energy metabolism results in decreases in high-energy phosphate stores and a deteriorating membrane potential. Under these conditions, the voltage-sensitive Mg2+ block of NMDA receptors is relieved, allowing the receptors to be persistently activated by endogenous concentrations of glutamate. In this way, metabolic defects may lead to neuronal death by a slow 'excitotoxic' mechanism. Recent studies indicate that such a mechanism occurs in vivo, and it may play a role in animal models of Huntington's disease and Parkinson's disease. ff a similar mechanism occurs in neurodegenerative diseases in humans it may be possible to use either excitatory amino acid antagonists or agents to improve neuronal bioenergenetics as therapeutic treatments for these disorders.