A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease
Identifieur interne : 002D85 ( Main/Corpus ); précédent : 002D84; suivant : 002D86A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease
Auteurs : C. Savio Chan ; Tracy S. Gertler ; D. James SurmeierSource :
- Movement Disorders [ 0885-3185 ] ; 2010.
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- KwdEn :
Abstract
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 Ca2+ 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 Ca2+ 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. © 2010 Movement Disorder Society
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DOI: 10.1002/mds.22801
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ISTEX:F06FD358D4702CA09D2BABC47AC253B64B3C65A1Le document en format XML
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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 Ca2+ 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 Ca2+ 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. © 2010 Movement Disorder Society</abstract><note type="content">*Potential conflict of interest: None.</note><subject lang="en"><genre>Keywords</genre><topic>Parkinson's disease</topic><topic>substantia nigra</topic><topic>dopamine</topic><topic>neurons</topic><topic>aging</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov. 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