title: Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice.
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.
authors.affiliation: Division of Genetics and Cell Biology and 2 Division of Neuroscience, San Raffaele Scientific Institute, DIBIT, 20132 Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Antonio
authors.forename: Nicolò
authors.initials: N
authors.lastname: Musner
authors.forename: Cristina
authors.initials: C
authors.lastname: Scapin
authors.forename: Daniela
authors.initials: D
authors.lastname: Ungaro
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
chemical_list: C497250:Ddit3 protein, mouse; D018993:Myelin P0 Protein; D051742:Transcription Factor CHOP; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1
references.citation: Neuron. 2001 May;30(2):355-68
references.pmid: 11394999
references.citation: Am J Pathol. 2008 Nov;173(5):1508-17
references.pmid: 18818381
references.citation: Nature. 2012 May 06;485(7399):507-11
references.pmid: 22622579
references.citation: Cell. 1992 Nov 13;71(4):565-76
references.pmid: 1384988
references.citation: Genes Dev. 2004 Dec 15;18(24):3066-77
references.pmid: 15601821
references.citation: Mol Cell. 2001 Jun;7(6):1165-76
references.pmid: 11430820
references.citation: Nat Neurosci. 2009 May;12(5):627-36
references.pmid: 19330001
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Glia. 2006 Sep;54(4):243-57
references.pmid: 16856148
references.citation: Nat Genet. 1993 Sep;5(1):35-9
references.pmid: 7693130
references.citation: Science. 2011 Apr 1;332(6025):91-4
references.pmid: 21385720
references.citation: Biochem Biophys Res Commun. 2009 Sep 25;387(3):504-10
references.pmid: 19615339
references.citation: Science. 2005 Feb 11;307(5711):935-9
references.pmid: 15705855
references.citation: J Neurosci. 2006 Feb 22;26(8):2358-68
references.pmid: 16495463
references.citation: J Cell Biol. 2000 Mar 6;148(5):1021-34
references.pmid: 10704451
references.citation: Eur J Neurosci. 1999 May;11(5):1577-86
references.pmid: 10215910
references.citation: Neurobiol Dis. 2009 Apr;34(1):146-54
references.pmid: 19320048
references.citation: J Biol Chem. 2008 Jun 27;283(26):18187-97
references.pmid: 18456662
references.citation: Cell Metab. 2009 Jul;10(1):13-26
references.pmid: 19583950
references.citation: J Neurosci. 2010 Aug 25;30(34):11388-97
references.pmid: 20739560
references.citation: Neuron. 2002 Nov 14;36(4):585-96
references.pmid: 12441049
references.citation: Dis Model Mech. 2013 Jan;6(1):135-45
references.pmid: 22864019
references.citation: Science. 2001 Apr 27;292(5517):727-30
references.pmid: 11326099
references.citation: Glia. 1996 Aug;17(4):294-306
references.pmid: 8856326
references.citation: Glia. 2008 Nov 1;56(14):1578-89
references.pmid: 18803325
references.citation: Genome Biol. 2005;6(9):R81
references.pmid: 16168088
references.citation: Neurobiol Dis. 2002 Oct;11(1):43-52
references.pmid: 12460545
references.citation: Brain. 2012 Jul;135(Pt 7):2032-47
references.pmid: 22689911
references.citation: J Biol Chem. 1999 Oct 29;274(44):31139-44
references.pmid: 10531303
references.citation: Glia. 2008 Nov 1;56(14):1541-51
references.pmid: 18803322
references.citation: Science. 2007 Nov 9;318(5852):944-9
references.pmid: 17991856
references.citation: Genes Dev. 1998 Apr 1;12(7):982-95
references.pmid: 9531536
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8998-9003
references.pmid: 12084938
references.citation: Neurobiol Dis. 2008 Oct;32(1):105-15
references.pmid: 18655835
references.citation: J Cell Biol. 2008 May 19;181(4):625-37
references.pmid: 18490512
references.citation: Nat Cell Biol. 2011 Mar;13(3):184-90
references.pmid: 21364565
references.citation: J Peripher Nerv Syst. 2012 Jun;17(2):197-200
references.pmid: 22734905
references.citation: J Cell Biol. 2006 Jan 30;172(3):383-93
references.pmid: 16449189
references.citation: J Neurosci Res. 2002 Jun 1;68(5):522-34
references.pmid: 12111842
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2596-601
references.pmid: 15695336
references.citation: J Neurosci Res. 2006 Aug 15;84(3):542-52
references.pmid: 16786575
references.citation: Biochem Biophys Res Commun. 2001 Jan 12;280(1):407-14
references.pmid: 11162531
references.citation: Glia. 2006 Apr 1;53(5):501-15
references.pmid: 16369933
references.citation: Mol Cell Neurosci. 1997 Jan;9(1):13-25
references.pmid: 9204477
references.citation: Neuron. 2005 Sep 1;47(5):681-94
references.pmid: 16129398
references.citation: PLoS Biol. 2007 Mar;5(3):e44
references.pmid: 17298185
references.citation: FASEB J. 2003 Aug;17(11):1573-5
references.pmid: 12824288
references.citation: Lancet Neurol. 2006 May;5(5):413-23
references.pmid: 16632312
references.citation: Mol Cell. 2000 Nov;6(5):1099-108
references.pmid: 11106749
references.citation: J Neurosci Res. 2012 Jan;90(1):96-104
references.pmid: 21932366
references.citation: Genes Dev. 2003 Oct 1;17(19):2450-64
references.pmid: 14522948
references.citation: Neurobiol Dis. 2007 Feb;25(2):252-65
references.pmid: 17174099
references.citation: J Biol Chem. 2009 Mar 13;284(11):6661-73
references.pmid: 19131336
references.citation: Nature. 1994 Oct 27;371(6500):796-9
references.pmid: 7935840
references.citation: J Neurosci Res. 2009 Nov 15;87(15):3241-9
references.pmid: 19330777
references.citation: Neuron. 2012 Aug 23;75(4):633-47
references.pmid: 22920255
references.citation: J Neurochem. 2006 Mar;96(5):1441-57
references.pmid: 16478531
references.citation: Nat Neurosci. 2009 Apr;12(4):379-85
references.pmid: 19287390
references.citation: Neurobiol Dis. 2000 Dec;7(6 Pt B):561-73
references.pmid: 11114256
references.citation: J Neurosci. 2011 Nov 9;31(45):16369-86
references.pmid: 22072688
references.citation: J Biol Chem. 2001 Sep 7;276(36):34131-41
references.pmid: 11427537
references.citation: PLoS Biol. 2006 Nov;4(11):e374
references.pmid: 17090218
references.citation: EMBO J. 2003 Mar 3;22(5):1180-7
references.pmid: 12606582
references.citation: Neurobiol Dis. 2005 Apr;18(3):656-68
references.pmid: 15755691
references.citation: EMBO J. 2004 Feb 25;23(4):950-8
references.pmid: 14765107
references.citation: Nature. 2000 Jan 6;403(6765):98-103
references.pmid: 10638761
references.citation: J Cell Biol. 2001 May 28;153(5):1011-22
references.pmid: 11381086
references.citation: J Neurochem. 2005 May;93(3):737-48
references.pmid: 15836632
references.citation: J Cell Biol. 2007 Jun 18;177(6):1063-75
references.pmid: 17576799
references.citation: Neuron. 2008 Feb 7;57(3):393-405
references.pmid: 18255032
references.citation: Curr Opin Neurobiol. 2009 Oct;19(5):505-10
references.pmid: 19744850
references.citation: Annu Rev Cell Dev Biol. 2002;18:575-99
references.pmid: 12142265
references.citation: EMBO J. 2005 Mar 23;24(6):1243-55
references.pmid: 15775988
references.citation: J Neurosci. 2003 Nov 19;23(33):10672-80
references.pmid: 14627652
references.citation: J Neurochem. 2002 Sep;82(5):1129-36
references.pmid: 12358760