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BIOLOGICAL SCIENCES / NEUROSCIENCE
RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals
*Department of Neurodegeneration and Restorative Research, Centers of Molecular Physiology of the Brain and Neurological Medicine, University of Goettingen, Waldweg 33, D-37073 Goettingen, Germany; and Department of Molecular Neurobiology, Max–Planck Institute of Neurobiology, Am Klopferspitz 18, D-82152 Martinsried, Germany
Edited by Hans Thoenen, Max Planck Institute of Neurobiology, Martinsried, Germany, and approved October 23, 2007 (received for review July 2, 2007)
Activation of the RET (rearranged during transfection) receptor by glial cell-line-derived neurotrophic factor (GDNF) has been identified as an important differentiation and survival factor for dopaminergic neurons of the midbrain in preclinical experiments. These encouraging results have led to clinical trials of GDNF in patients with Parkinson's disease, which have resulted in conflicting findings. To investigate the potential benefit of Ret-dependent signaling on the challenged dopaminergic system, we tested the effect of tissue-selective ablation of the Ret gene on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, the most widely used animal model for Parkinson's disease. Ablation of Ret did not modify the MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and the dopaminergic innervation of the striatum at 14 days. However, Ret ablation abolished the regeneration of dopaminergic fibers and terminals, as well as the partial recovery of striatal dopamine concentrations, that was observed in control mice between days 14 and 90 after MPTP treatment. We therefore conclude that RET signaling has no influence on the survival of dopaminergic neurons in the MPTP model of Parkinson's disease but rather facilitates the regeneration of dopaminergic axon terminals.
Parkinson's disease | 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine | glial cell-line-derived neurotrophic factor | neuroprotection
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706177104/DC1
To whom correspondence should be addressed. E-mail: jschulz4{at}gwdg.de
© 2007 by The National Academy of Sciences of the USA
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