Parkinson's Disease: The Link Between Monoamine Oxidase and Mitochondrial Respiration.

摘要

Parkinson s disease (PD) is a common chronic neurodegenerative disorder affecting one per one hundred adults over age 50. The underlying cause(s) of PD remain unknown. Dr. Cohen, the original recipient of the grant, titled Parkinson s Disease; the link between monoamine oxidase (MAO) and mitochondrial respiration , proposed that the dopaminemetabolizing enzyme monoamine oxidase could potentially injure dopaminergic neurons; mediated initially by the formation of hydrogen peroxide and subsequently its conversion to water at the expense of formation of glutathione disulfide, catalyzed by glutathione peroxidase. The formation of the electrophilic glutathione disulfide in principle, and subsequently demonstrated experimentally, is able to subsequently form protein-cysteinyl-thiol-glutathione mixed disulfides (Pro-Cys-S-S-Glu). As Dr. Cohen was an expert in studying mitochondrial function, he further proposed that Pro-Cys-S-S-Glu mixed disulfides could lead to inhibition of electron transport chain function as a result of chemical modification of critical protein thiols in the mitochondrial electron transport chain. Depriving dopaminergic neurons of energy as a result of modification of critically-important thiolmoieties in mitochondria could secondarily lead to neuronal injury and death, providing a potential pathway contributing to the development of Parkinson s Disease. Whereas Dr Cohen focused on monoamine oxidase, my colleagues and I characterized a second mitochondrial inhibitory pathway involving catechol-oxidative pathways independent of MAO.