Calcium, ageing, and neuronal vulnerability in Parkinson's disease.
Parkinson's disease is a common neurodegenerative disorder of unknown cause. 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 Parkinson's disease 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 their increasing reliance on Ca(2+) channels to maintain autonomous activity with age. This reliance could pose a sustained metabolic stress on mitochondria, accelerating cellular ageing and death. The Ca(2+) channels underlying autonomous activity in dopaminergic neurons are closely related to the L-type channels found in the heart and smooth muscle. Systemic administration of isradipine, a dihydropyridine blocker of L-type channels, forces dopaminergic neurons in rodents to revert to a juvenile, Ca(2+)-independent mechanism to generate autonomous activity. More importantly, reversion confers protection against toxins that produce experimental parkinsonism, pointing to a potential neuroprotective strategy for Parkinson's disease with a drug class that has been used safely in human beings for decades. These studies also suggest that, although genetic and environmental factors can hasten its onset, Parkinson's disease stems from a distinctive neuronal design common to all human beings, making its appearance simply a matter of time.
Surmeier
D James
DJ
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. j-surmeier@northwestern.edu
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D017275:Isradipine / Q000494:pharmacology; D009410:Nerve Degeneration / Q000209:etiology* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000150:complications* / Q000517:prevention & control; D020734:Parkinsonian Disorders / Q000517:prevention & control; D013378:Substantia Nigra / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018696:Neuroprotective Agents; D002118:Calcium; D004298:Dopamine; D017275:Isradipine