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Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice.

D'Antonio, M; Musner, N; Scapin, C; Ungaro, D; Del Carro, U; Ron, D; Feltri, ML; (2013) Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. J Exp Med , 210 (4) pp. 821-838. 10.1084/jem.20122005.

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Abstract

P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.

Type: Article
Title: Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice.
Location: United States
DOI: 10.1084/jem.20122005
Keywords: Animals, Cell Differentiation, Charcot-Marie-Tooth Disease, Disease Models, Animal, Humans, Mice, Mice, Mutant Strains, Myelin P0 Protein, Myelin Sheath, Protein Phosphatase 1, Sequence Deletion, Transcription Factor CHOP
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1391021
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