The origins of oxidant stress in Parkinson's disease and therapeutic strategies.
Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.
Surmeier
Dalton James
DJ
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Guzman
Jaime N
JN
Sanchez-Padilla
Javier
J
Goldberg
Joshua A
JA
D000375:Aging; D000818:Animals; D001683:Biological Clocks; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D016923:Cell Death; D006801:Humans; D017275:Isradipine / Q000494:pharmacology; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species; D017275:Isradipine