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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...

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Autores principales: Goebbels, Sandra, Oltrogge, Jan H, Wolfer, Susanne, Wieser, Georg L, Nientiedt, Tobias, Pieper, Alexander, Ruhwedel, Torben, Groszer, Matthias, Sereda, Michael W, Nave, Klaus-Armin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2012
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.
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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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