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Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System
Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808500/ https://www.ncbi.nlm.nih.gov/pubmed/17298183 http://dx.doi.org/10.1371/journal.pbio.0050039 |
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author | Kramer, Edgar R Aron, Liviu Ramakers, Geert M. J Seitz, Sabine Zhuang, Xiaoxi Beyer, Klaus Smidt, Marten P Klein, Rüdiger |
author_facet | Kramer, Edgar R Aron, Liviu Ramakers, Geert M. J Seitz, Sabine Zhuang, Xiaoxi Beyer, Klaus Smidt, Marten P Klein, Rüdiger |
author_sort | Kramer, Edgar R |
collection | PubMed |
description | Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD. |
format | Text |
id | pubmed-1808500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-18085002007-03-14 Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System Kramer, Edgar R Aron, Liviu Ramakers, Geert M. J Seitz, Sabine Zhuang, Xiaoxi Beyer, Klaus Smidt, Marten P Klein, Rüdiger PLoS Biol Research Article Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD. Public Library of Science 2007-03 2007-02-13 /pmc/articles/PMC1808500/ /pubmed/17298183 http://dx.doi.org/10.1371/journal.pbio.0050039 Text en © 2007 Kramer et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kramer, Edgar R Aron, Liviu Ramakers, Geert M. J Seitz, Sabine Zhuang, Xiaoxi Beyer, Klaus Smidt, Marten P Klein, Rüdiger Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System |
title | Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System |
title_full | Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System |
title_fullStr | Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System |
title_full_unstemmed | Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System |
title_short | Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System |
title_sort | absence of ret signaling in mice causes progressive and late degeneration of the nigrostriatal system |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808500/ https://www.ncbi.nlm.nih.gov/pubmed/17298183 http://dx.doi.org/10.1371/journal.pbio.0050039 |
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