期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 4, 期 142, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3003799
关键词
-
资金
- Hereditary Disease Foundation
- Cure Huntington's Disease Initiative
- NIH [R01 AG033082, R01 NS065874, P01 HL034322, R01 AG018440, R01 NS057096, R01 AG022074]
Huntington's disease (HD) is caused by CAG repeat expansions in the huntingtin (htt) gene, yielding proteins containing polyglutamine repeats that become misfolded and resist degradation. Previous studies demonstrated that mutant htt interferes with transcriptional programs coordinated by the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha), a regulator of mitochondrial biogenesis and oxidative stress. We tested whether restoration of PGC-1 alpha could ameliorate the symptoms of HD in a mouse model. We found that PGC-1 alpha induction virtually eliminated htt protein aggregation and ameliorated HD neurodegeneration in part by attenuating oxidative stress. PGC-1 alpha promoted htt turnover and the elimination of protein aggregates by activating transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. TFEB alone was capable of reducing htt aggregation and neurotoxicity, placing PGC-1 alpha upstream of TFEB and identifying these two molecules as important therapeutic targets in HD and potentially other neurodegenerative disorders caused by protein misfolding.
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