Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in charcot-marie-tooth 1B mice (Neuron, 2008, 57:393-405)

報告日期: 2008/11/28
報告時間: 16:00/16:50
報告學生: 趙詠梅
講評老師: 黃朝慶


Ablation of the UPR-Mediator CHOP Restores Motor Function and Reduces Demyelination in Charcot-Marie-Tooth 1B Mice


Pennuto M., Tinelli E., Malaguti M., Carro UD., D’Antonio M., Ron D., Quattrini A., Feltri ML., and Wrabetz L.

Neuron, 2008, 57:393-405


Speaker: 趙詠梅

Commentator: Dr. 黃朝慶

Time: 2008/11/28 pm 4:00~4:50

Place: R602



    Charcot-Marie-Tooth (CMT) neuropathies are characterized by progressive distal weakness and muscle atrophy, foot deformities, impaired tendon reflexes, and usually minor sensory symptoms. Deletion of serine 63 from Myelin Protein Zero (P0) glycoprotein (P0S63del) causes CMT 1B neuropathy in humans, and P0S63del produces a similar demyelinating neuropathy in transgenic mice. The authors hypothesize that P0S63del is misfolded in the endoplasmic reticulum (ER) and Schwann cells that mainly provide myelin insulation to axons in the peripheral nervous system causing a consequential canonical unfolded protein response (UPR). To examine the hypothesis, the authors used P0S63del transgenic mice and wide-type mice in the study. They reported that P0S63del activates a canonical and dose-dependent UPR, including expression of the transcription factor CHOP, which is associated with apoptosis in ER-stressed cells, and consequentially demyelination in Schwann cells. UPR activation and CHOP expression respond dynamically to P0S63del levels but are associated with only limited apoptosis of Schwann cells. Ablation of Chop in S63del mice reverses behavioral, electrophysiological, and morphological abnormalities, indicating the UPR as a novel pathogenetic mechanism in demyelinating peripheral neuropathies. These results indicate that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. S63del mice also provides an opportunity to explore how cells can dysfunction yet survive in prolonged ER stress, cellular events that are important for neurodegeneration related to misfolded proteins. Mechanisms identified in this model may be relevant to other misfolded protein diseases, such as Alzheimer’s or Parkinson’s disease or diaetes.



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