Constitutive Ret signaling is protective for dopaminergic cell bodies but not for axonal terminals.

Abstract

Ret is the canonical signaling receptor for glial cell line-derived neurotrophic factor (GDNF), which has been shown to have neuroprotective effects when administered prior to neurotoxic challenge. A missense Meth918Thr mutation causes the constitutive activation of Ret, resulting in multiple endocrine neoplasia type 2 B (MEN2B). To clarify the role of Ret signaling in neuroprotection, we studied the effects of the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) on the dopaminergic system of mice carrying the MEN2B mutation. We found that MEN2B mice were significantly more resistant to nigral tyrosine hydroxylase (TH)-positive cell loss induced by unilateral striatal 6-OHDA than Wt mice. However, 6-OHDA caused profound dopamine (DA) depletion in the striatum of both MEN2B and Wt mice. Systemic MPTP caused similar DA depletion and a decrease in TH-immunostaining in the striatum of MEN2B and Wt mice. Neither neurotoxin induced a compensatory increase in striatal metabolite/DA ratios in the MEN2B mice, possibly contributing to an increased amphetamine-induced turning behavior observed in behavioral assessments of these mice. Thus, our data suggest that activated Ret protects DA cell bodies in the substantia nigra pars compacta, but does not protect DA axons in the striatum.

• Authors: Jelena Mijatovic, Marjo Piltonen, Paolo Alberton, Pekka T Männistö, Mart Saarma, T Petteri Piepponen
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 32 Issue 8 Pg. 1486-94 (Aug 2011) ISSN: 1558-1497 [Electronic] United States
• PMID: 19767128 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2009 Elsevier Inc. All rights reserved.

Chemical References

• Proto-Oncogene Proteins c-ret
• Ret protein, mouse
• Dopamine

Topics

• Animals
• Corpus Striatum (pathology, physiology)
• Dopamine (physiology)
• Gene Knock-In Techniques (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Neurons (pathology, physiology)
• Parkinsonian Disorders (genetics, metabolism, pathology)
• Presynaptic Terminals (pathology, physiology)
• Proto-Oncogene Proteins c-ret (genetics, physiology)
• Signal Transduction (genetics)