STM：PGC-1α和TFEB两种蛋白可治疗亨廷顿氏病

近日，刊登在国际杂志Science Translational Medicine上的一篇研究报告中，研究人员发现了错误折叠的蛋白是如何从患有亨廷顿氏病的脑中被清除的。提高2种参与该过程的关键性调节蛋白——PGC-1alpha 和TFEB——的水平可能可以治疗亨廷顿氏病及其它的神经退行性疾病。

Taiji Tsunemi及其同事在他们试验中改变了罹患亨廷顿氏病的小鼠基因，使其能产生更多的PGC-1alpha。PGC-1alpha的增加清除了错误折叠的亨廷顿蛋白团块并消除了这些动物中的神经学症状。在经过进一步的探索之后，该团队发现，PGC-1alpha是通过激活那些会遏制脑中的叫做活性氧族物质的危险的化学性化合物而发挥作用的。

PGC-1alpha还可启动TFEB的运作——TFEB这种蛋白可帮助从细胞中清除受损的线粒体。如果科学家们能够找到增加PGC-1alpha或TFEB中任一蛋白的作用的方式，这种方法可能会对亨廷顿氏病患者有益。

doi:10.1126/scitranslmed.3003799
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PGC-1α Rescues Huntington’s Disease Proteotoxicity by Preventing Oxidative Stress and Promoting TFEB Function

Taiji Tsunemi1, Travis D. Ashe1, Bradley E. Morrison1, Kathryn R. Soriano2, Jonathan Au2, Ruben A. Vázquez Roque3, Eduardo R. Lazarowski4, Vincent A. Damian2, Eliezer Masliah3,5 and Albert R. La Spada1,5,6,7,8,9,10,*

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 γ (PPARγ) coactivator 1α (PGC-1α), a regulator of mitochondrial biogenesis and oxidative stress. We tested whether restoration of PGC-1α could ameliorate the symptoms of HD in a mouse model. We found that PGC-1α induction virtually eliminated htt protein aggregation and ameliorated HD neurodegeneration in part by attenuating oxidative stress. PGC-1α 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-1α upstream of TFEB and identifying these two molecules as important therapeutic targets in HD and potentially other neurodegenerative disorders caused by protein misfolding.