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 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 misfolded and Schwann cells mount a consequential canonical unfolded protein response (UPR), including 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 2-fold. This indicates that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. S63del mice also provide an opportunity to explore how cells can dysfunction yet survive in prolonged ER stress-important for neurodegeneration related to misfolded proteins.
Pennuto
Maria
M
DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Tinelli
Elisa
E
Malaguti
Mariachiara
M
Del Carro
Ubaldo
U
D'Antonio
Maurizio
M
Ron
David
D
Quattrini
Angelo
A
Feltri
M Laura
ML
Wrabetz
Lawrence
L
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D016466:CHO Cells; D002607:Charcot-Marie-Tooth Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D003711:Demyelinating Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D018993:Myelin P0 Protein / Q000235:genetics; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000172:deficiency*; D014162:Transfection / Q000379:methods
C497250:Ddit3 protein, mouse; D018993:Myelin P0 Protein; D051742:Transcription Factor CHOP; D001973:Bromodeoxyuridine