Ret is essential to mediate GDNF's neuroprotective and neuroregenerative effect in a Parkinson disease mouse model.
Glial cell line-derived neurotrophic factor (GDNF) is a potent survival and regeneration-promoting factor for dopaminergic neurons in cell and animal models of Parkinson disease (PD). GDNF is currently tested in clinical trials on PD patients with so far inconclusive results. The receptor tyrosine kinase Ret is the canonical GDNF receptor, but several alternative GDNF receptors have been proposed, raising the question of which signaling receptor mediates here the beneficial GDNF effects. To address this question we overexpressed GDNF in the striatum of mice deficient for Ret in dopaminergic neurons and subsequently challenged these mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Strikingly, in this established PD mouse model, the absence of Ret completely abolished GDNF's neuroprotective and regenerative effect on the midbrain dopaminergic system. This establishes Ret signaling as absolutely required for GDNF's effects to prevent and compensate dopaminergic system degeneration and suggests Ret activation as the primary target of GDNF therapy in PD.
DFG Research Center Molecular Physiology of the Brain (CMPB), University Medical Center Göttingen, Göttingen, Germany.|Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
Anja
A
Drinkut
Development and Maintenance of the Nervous System, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Karsten
K
Tillack
Development and Maintenance of the Nervous System, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Durga P
DP
Meka
DFG Research Center Molecular Physiology of the Brain (CMPB), University Medical Center Göttingen, Göttingen, Germany.|Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.|Department of Neurology and JARA BRAIN Institute II, RWTH Aachen University and FZ Jülich, Aachen, Germany.
Jorg B
JB
Schulz
DFG Research Center Molecular Physiology of the Brain (CMPB), University Medical Center Göttingen, Göttingen, Germany.|Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Sebastian
S
Kügler
Development and Maintenance of the Nervous System, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Applied Physiology, Ulm University, Ulm, Germany.
Edgar R
ER
Kramer
D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse