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Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy
‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by u...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
WILEY-VCH Verlag
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443946/ https://www.ncbi.nlm.nih.gov/pubmed/22488882 http://dx.doi.org/10.1002/emmm.201200227 |
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author | Goebbels, Sandra Oltrogge, Jan H Wolfer, Susanne Wieser, Georg L Nientiedt, Tobias Pieper, Alexander Ruhwedel, Torben Groszer, Matthias Sereda, Michael W Nave, Klaus-Armin |
author_facet | Goebbels, Sandra Oltrogge, Jan H Wolfer, Susanne Wieser, Georg L Nientiedt, Tobias Pieper, Alexander Ruhwedel, Torben Groszer, Matthias Sereda, Michael W Nave, Klaus-Armin |
author_sort | Goebbels, Sandra |
collection | PubMed |
description | ‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P(3) at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies. |
format | Online Article Text |
id | pubmed-3443946 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-34439462012-09-17 Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy Goebbels, Sandra Oltrogge, Jan H Wolfer, Susanne Wieser, Georg L Nientiedt, Tobias Pieper, Alexander Ruhwedel, Torben Groszer, Matthias Sereda, Michael W Nave, Klaus-Armin EMBO Mol Med Research Articles ‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P(3) at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies. WILEY-VCH Verlag 2012-06 2012-04-04 /pmc/articles/PMC3443946/ /pubmed/22488882 http://dx.doi.org/10.1002/emmm.201200227 Text en Copyright © 2012 EMBO Molecular Medicine |
spellingShingle | Research Articles Goebbels, Sandra Oltrogge, Jan H Wolfer, Susanne Wieser, Georg L Nientiedt, Tobias Pieper, Alexander Ruhwedel, Torben Groszer, Matthias Sereda, Michael W Nave, Klaus-Armin Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy |
title | Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy |
title_full | Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy |
title_fullStr | Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy |
title_full_unstemmed | Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy |
title_short | Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy |
title_sort | genetic disruption of pten in a novel mouse model of tomaculous neuropathy |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443946/ https://www.ncbi.nlm.nih.gov/pubmed/22488882 http://dx.doi.org/10.1002/emmm.201200227 |
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