PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function.
PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function.
复制标题
DOI：
10.1126/scitranslmed.3003799
复制
发表时间：
2012-07-11
影响因子：
17.1
通讯作者：
La Spada AR
中科院分区：
文献类型：
--
作者：
Tsunemi T;Ashe TD;Morrison BE;Soriano KR;Au J;Roque RA;Lazarowski ER;Damian VA;Masliah E;La Spada AR
亨廷顿病(HD)是由亨廷顿蛋白(HTT)基因中CAG/聚谷氨酰胺重复扩张引起的，产生的蛋白质错误折叠并抵抗降解。HD属于一大类神经退行性蛋白质病，包括阿尔茨海默病、帕金森氏病和神经官能症。以前的研究表明，突变的hTt干扰由PPARγ共激活因子1α(pGC-1α)协调的转录程序，pGC-1是线粒体生物发生和氧化应激的调节因子。为了测试修复pgc-1α是否可以治疗HD，我们尝试了在小鼠身上进行体内遗传拯救。我们发现，pGC-1α诱导可改善HD神经退行性变，并几乎消除HTT蛋白聚集，部分原因是通过减轻氧化应激。进一步的研究表明，PGC-1α通过反式激活自噬-溶酶体途径的主要调节因子TFEB来促进HTT的周转和聚集消除，并且TFEB单独能够减少HTT的聚集和神经毒性，将PGC-1α置于TFEB的上游。因此，PGC-1、α和TFEB作为HD和其他神经退行性蛋白病的治疗方法具有很大的前景。
Huntington’s disease (HD) is caused by CAG / polyglutamine repeat expansions in the huntingtin (htt) gene, yielding proteins that misfold and resist degradation. HD belongs to a large class of neurodegenerative proteinopathies including Alzheimer’s disease, Parkinson’s disease, and tauopathies. Previous studies demonstrated that mutant htt interferes with transcriptional programs coordinated by PPARγ co-activator 1α (PGC-1α), a regulator of mitochondrial biogenesis and oxidative stress. To test if restoration of PGC-1α could treat HD, we attempted an in vivo genetic rescue in mice. We found that PGC-1α induction ameliorates HD neurodegeneration and virtually eliminates htt protein aggregation, in part by attenuating oxidative stress. Further studies revealed that PGC-1α promotes htt turnover and aggregate elimination by transactivation of TFEB, a master regulator of the autophagy-lysosome pathway, and that TFEB alone is capable of reducing htt aggregation and neurotoxicity, placing PGC-1α upstream of TFEB. PGC-1α and TFEB thus hold great promise as therapies for HD and other neurodegenerative proteinopathies.
登录
查看更多内容
影响因子：
3.7
作者：
Clark J;Clore EL;Zheng K;Adame A;Masliah E;Simon DK
通讯作者：
Simon DK
影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
影响因子：
3.5
作者：
Choo, YS;Johnson, GVW;Lesort, M
通讯作者：
Lesort, M
DOI：
10.1097/00005072-199711000-00004
发表时间：
1997-11-01
影响因子：
3.2
作者：
Everall, IP;DeTeresa, R;Masliah, E
通讯作者：
Masliah, E
影响因子：
64.5
作者：
Lin, JD;Wu, PH;Spiegelman, BM
通讯作者：
Spiegelman, BM