ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE

Deletion of serine 63 from P0 glycoprotein (P0S63del) causes Charcot-Marie-Tooth 1B neuropathy in humans, and P0S63del produces a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that...

Disgrifiad llawn

Wedi'i Gadw mewn:
Manylion Llyfryddiaeth
Prif Awduron: Pennuto, Maria, Tinelli, Elisa, Malaguti, MariaChiara, Del Carro, Ubaldo, D'Antonio, Maurizio, Ron, David, Quattrini, Angelo, Feltri, M. Laura, Wrabetz, Lawrence
Fformat: Erthygl
Iaith:English
Cyhoeddwyd: 2008
Pynciau:
Article
Mynediad Ar-lein:https://ncbi.nlm.nih.gov/pmc/articles/PMC2267889/
https://ncbi.nlm.nih.gov/pubmed/18255032
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1016/j.neuron.2007.12.021
Tagiau: Ychwanegu Tag
Dim Tagiau, Byddwch y cyntaf i dagio'r cofnod hwn!
id pubmed-2267889
record_format dspace
spelling pubmed-22678892009-02-07 ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE Pennuto, Maria Tinelli, Elisa Malaguti, MariaChiara Del Carro, Ubaldo D'Antonio, Maurizio Ron, David Quattrini, Angelo Feltri, M. Laura Wrabetz, Lawrence Neuron Article Deletion of serine 63 from P0 glycoprotein (P0S63del) causes Charcot-Marie-Tooth 1B neuropathy in humans, and P0S63del produces a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that P0S63del is globally misfolded and Schwann cells mount a consequential canonical unfolded protein response (UPR), that includes expression of the transcription factor CHOP, previously associated with apoptosis in ER-stressed cells. UPR activation and CHOP expression respond dynamically to P0S63del levels and are reversible, but are associated with only limited apoptosis of Schwann cells. Nonetheless, Chop ablation in S63del mice completely rescues their motor deficit and reduces active demyelination two-fold. This is the first indication that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. In addition, S63del mice provide a unique opportunity to explore how cells can dysfunction yet survive in prolonged ER stress—important for neurodegeneration related to misfolded proteins. 2008-02-07 /pmc/articles/PMC2267889/ /pubmed/18255032 http://dx.doi.org/10.1016/j.neuron.2007.12.021 Text en
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Article
spellingShingle Article
Pennuto, Maria
Tinelli, Elisa
Malaguti, MariaChiara
Del Carro, Ubaldo
D'Antonio, Maurizio
Ron, David
Quattrini, Angelo
Feltri, M. Laura
Wrabetz, Lawrence
ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE
description Deletion of serine 63 from P0 glycoprotein (P0S63del) causes Charcot-Marie-Tooth 1B neuropathy in humans, and P0S63del produces a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that P0S63del is globally misfolded and Schwann cells mount a consequential canonical unfolded protein response (UPR), that includes expression of the transcription factor CHOP, previously associated with apoptosis in ER-stressed cells. UPR activation and CHOP expression respond dynamically to P0S63del levels and are reversible, but are associated with only limited apoptosis of Schwann cells. Nonetheless, Chop ablation in S63del mice completely rescues their motor deficit and reduces active demyelination two-fold. This is the first indication that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. In addition, S63del mice provide a unique opportunity to explore how cells can dysfunction yet survive in prolonged ER stress—important for neurodegeneration related to misfolded proteins.
author Pennuto, Maria
Tinelli, Elisa
Malaguti, MariaChiara
Del Carro, Ubaldo
D'Antonio, Maurizio
Ron, David
Quattrini, Angelo
Feltri, M. Laura
Wrabetz, Lawrence
author_facet Pennuto, Maria
Tinelli, Elisa
Malaguti, MariaChiara
Del Carro, Ubaldo
D'Antonio, Maurizio
Ron, David
Quattrini, Angelo
Feltri, M. Laura
Wrabetz, Lawrence
author_sort Pennuto, Maria
title ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE
title_short ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE
title_full ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE
title_fullStr ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE
title_full_unstemmed ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE
title_sort ablation of the upr–mediator chop restores motor function and reduces demyelination in charcot marie tooth 1b mice
publishDate 2008
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2267889/
https://ncbi.nlm.nih.gov/pubmed/18255032
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1016/j.neuron.2007.12.021
_version_ 1760531396856643584

Eitemau Tebyg