Rapid down-regulation of Ret following exposure of dopaminergic neurons to neurotoxins

The survival and functional maintenance of vertebrate neurons depends on the availability of specific neurotrophic factors. We studied the influence of neurotrophic support on responses of dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin known to damage the nigrostriatal dopaminergic pathway in humans and other mammals. Treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine caused decreases in levels of Ret, a tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF) in the striatum, under the condition in which tyrosine hydroxylase was moderately decreased and the GDNF family receptor alpha1, another receptor of GDNF that is the ligand-binding subunit, were unaffected. Down-regulation of Ret was also observed in dopamine-producing PC12 cells undergoing apoptosis induced by rotenone, another toxic substance for dopaminergic neurons, while other cellular components were not affected. Ret was also extremely vulnerable to other apoptotic inducing conditions. Taken together, these results indicate that Ret, an important signal molecule in dopaminergic neurons, may be down-regulated in the early stages of neuronal degeneration caused by various neurotoxic substances, and may lead to reduced neurotrophic influences.