A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease.
Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L-type Ca(2+) channels with a pore-forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L-type Ca(2+) channel independent mechanism to generate autonomous activity. This "rejuvenation" confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD.
Chan
C Savio
CS
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Gertler
Tracy S
TS
Surmeier
D James
DJ
D000375:Aging; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D017275:Isradipine / Q000627:therapeutic use; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D013378:Substantia Nigra / Q000473:pathology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002118:Calcium; D004298:Dopamine; D017275:Isradipine