The molecular mechanism of dopamine-induced apoptosis: Identification and characterization of genes that mediate dopamine toxicity

A. Barzilai*, R. Zilkha-Falb, D. Daily, N. Stern, D. Offen, I. Ziv, E. Melamed, A. Shirvan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson's disease (PD) is a progressive neurological disorder caused by rather selective degeneration of the dopaminergic (DA) neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral neuronal loss is still enigmatic and treatment is basically symptomatic. The current major hypothesis suggests that nigral neuronal death in PD is due to excessive oxidative stress generated by auto- and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin and presence of high concentrations of iron. We have found that DA toxicity is mediated through its oxidative metabolites. Whereas thiol-containing antioxidants provided marked protection against DA toxicity, ascorbic acid accelerated DA-induced death. Using the differential display approach, we sought to isolate and characterize genes whose expression is altered in response to DA toxicity. We found an upregulation of the collapsin response mediator protein (CRM) and TCP-1δ in sympathetic neurons, which undergo dopamine-induced apoptosis. The isolation of these genes led us to examine the expression and activity of CRM and TCP-1δ related genes. Indeed, we found a significant induction of mRNAs of the secreted collapsin-1 and the mitochondrial stress protein HSP60. Antibodies directed against collapsin-1 provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. In a parallel study, using antisense technology, we found that inhibition of TCP-1δ expression significantly reduced DA-induced neuronal death. These findings suggest a functional role for collapsin-1 and TCP-1δ as positive mediators of DA-induced neuronal apoptosis.

Original languageEnglish
Pages (from-to)59-76
Number of pages18
JournalJournal of Neural Transmission, Supplement
Volume60
DOIs
StatePublished - 2000

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