What causes the death of dopaminergic neurons in Parkinson’s disease?

The factors governing neuronal loss in Parkinson’s disease (PD) are the subject of continuing speculation and experimental study. In recent years, factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discuss...

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Published inProgress in Brain Research Vol. 183; pp. 59 - 77
Main Authors Surmeier, D. James, Guzman, Jaime N., Sanchez-Padilla, Javier, Goldberg, Joshua A.
Format Book Chapter Journal Article
LanguageEnglish
Published Netherlands Elsevier Science & Technology 2010
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ISBN0444536140
9780444536143
ISSN0079-6123
1875-7855
1875-7855
DOI10.1016/S0079-6123(10)83004-3

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Summary:The factors governing neuronal loss in Parkinson’s disease (PD) are the subject of continuing speculation and experimental study. In recent years, factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease aetiology. 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 chapter focuses on recent studies showing that the neurons at greatest risk in PD – substantia nigra pars compacta (SNc) dopamine (DA) 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 SNc DA 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.
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ISBN:0444536140
9780444536143
ISSN:0079-6123
1875-7855
1875-7855
DOI:10.1016/S0079-6123(10)83004-3