CMAT 1B: Ablation of the UPR-Mediator CHOP Restores Motor Function and Reduces D

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Ablation of the UPR-Mediator CHOP Restores Motor Function and Reduces

Demyelination in Charcot-Marie-Tooth 1B Mice

Pennuto,1,4 Tinelli,1 Chiara Malaguti,2 Ubaldo Del

Carro,2 Maurizio D',1 Ron,3 Angelo Quattrini,2 M.

Feltri,1 and Lawrence Wrabetz1,

1 DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132

Milan, Italy

2 Department of Neurology, San Raffaele Scientific Institute, Via

Olgettina 58, 20132 Milan, Italy

3 Skirball Institute, New York University School of Medicine, New

York, NY 10016, USA

(this is the summary - full text article link is below ~ G)

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.

http://www.neuron.org/content/article/fulltext?

uid=PIIS0896627307010343