期刊
GENES & DEVELOPMENT
卷 23, 期 19, 页码 2294-2306出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1830709
关键词
Amyotrophic lateral sclerosis; unfolded protein response; endoplasmic reticulum stress; XBP-1; autophagy
资金
- Leila Y Mathers Charitable Foundation
- NIH [AI32412]
- Genzyme Sponsor Research Agreement
- FONDECYT [1070444, 3085017, 1070377, AG031782]
- FONDAP [15010006]
- Millennium Nucleus [P07-048-F]
- Muscular Dystrophy Association
- Michael J. Fox Foundation for Parkinson's Research
- National Parkinson Foundation
- High Q Foundation
- ICGEB
- ALSA-The Milton Safenowitz Post-Doctoral
- CONICYT Ph. D
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- Al-Athel ALS Research Foundation
- ALS Association
- ALS Therapy Alliance
- Angel Fund
- Project ALS
- Pierre L de Bourgknecht ALS Research Foundation
Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS). Recent evidence implicates adaptive responses to endoplasmic reticulum (ER) stress in the disease process via a pathway known as the unfolded protein response (UPR). Here, we investigated the contribution to fALS of X-box-binding protein-1 (XBP-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control. Despite expectations that XBP-1 deficiency would enhance the pathogenesis of mutant SOD1, we observed a dramatic decrease in its toxicity due to an enhanced clearance of mutant SOD1 aggregates by macroautophagy, a cellular pathway involved in lysosome-mediated protein degradation. To validate these observations in vivo, we generated mutant SOD1 transgenic mice with specific deletion of XBP-1 in the nervous system. XBP-1-deficient mice were more resistant to developing disease, correlating with increased levels of autophagy in motoneurons and reduced accumulation of mutant SOD1 aggregates in the spinal cord. Post-mortem spinal cord samples from patients with sporadic ALS and fALS displayed a marked activation of both the UPR and autophagy. Our results reveal a new function of XBP-1 in the control of autophagy and indicate critical cross-talk between these two signaling pathways that can provide protection against neurodegeneration.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据