Hypothesis: The role of dopaminergic transporters in selective vulnerability of cells in Parkinson's disease

G. R. Uhl

Research output: Contribution to journalArticle

Abstract

Many neurodegenerative disorders manifest especially severe losses of one or two specific neuronal populations on a background of less severe but more broadly distributed damage to other cell groups. PD displays prominent dopaminergic substantia nigra lesions as well as more variable, subtle, and multifocal destruction in other brain regions, including noradrenergic, serotoninergic, and cholinergic nuclei. The consistency of the dopaminergic lesions, the striking focality of these cell losses, and the ability to relate dopaminergic deficits to major motor symptoms of PD each suggest that any explanation for PD pathogenesis must explain the patterns of dopamine cell losses in PD brains. The causes of most cases of idiopathic PD remains unknown. However, the evidence cited here suggests that some causal events whose toxicity could be modulated by miscompartmentalization of dopamine or other toxins should be considered with special emphasis. Neurodegenerative mechanisms that could be modulated by transporter-based compartmentalization in dopaminergic neurons should receive special attention. Processes that could be exacerbated by the oxidative stresses conferred by cytoplasmic extravesicular dopamine are particularly interesting candidate mechanisms for PD. Identifying a transport-associated mechanism that explains selective losses in PD dopaminergic neurons could have several consequences. Drugs that up-regulate or enhance the functions of the vesicular transporter or those that inhibit intracellular uptake mediated by DAT would be of interest for therapeutic trials targeted toward slowing disease onset or progression. Such agents could act directly on these transporters, or could modulate transporter functions by, for example, altering their phosphorylation. Individual differences in DAT and VMAT2 expression, genetically or environmentally determined, could serve as markers for vulnerability to PD. Individuals with such vulnerabilities could be particularly good candidates for prophylactic strategies, including those modulating DAT and VMAT2 functions.

Original languageEnglish (US)
Pages (from-to)555-560
Number of pages6
JournalAnnals of Neurology
Volume43
Issue number5
DOIs
StatePublished - 1998

ASJC Scopus subject areas

  • Neuroscience(all)

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