Research ArticleHuntington’s Disease

PGC-1α Rescues Huntington’s Disease Proteotoxicity by Preventing Oxidative Stress and Promoting TFEB Function

Science Translational Medicine  11 Jul 2012:
Vol. 4, Issue 142, pp. 142ra97
DOI: 10.1126/scitranslmed.3003799

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From PGC-1α to TFEB: Mileposts in Huntington’s Disease

Huntington’s disease (HD) is an untreatable neurodegenerative disease caused by the production of huntingtin protein containing too many polyglutamine repeats. Patients with HD develop a progressive movement disorder and cognitive decline for which no suitable therapy is currently available. HD pathogenesis stems from mitochondrial dysfunction and altered transcription of nuclear genes, which has been linked to impaired action of the transcription factor PPARγ co-activator 1α (PGC-1α). In a new study, Tsunemi et al. tested whether increased PGC-1α function could ameliorate neuronal loss and some of the neurological symptoms of HD by crossing a mouse in which PGC-1α can be inducibly overexpressed with a transgenic mouse model of HD. The authors found that not only does PGC-1α overexpression improve neurological function in these mice, but it also virtually eradicates aggregates of mutant huntingtin protein in the brains of the HD mice. When they analyzed the reason for this genetic rescue in cultured cells and in the HD mice, they discovered that increased PGC-1α expression promoted mitochondrial function by boosting oxidative phosphorylation and reducing oxidative stress by turning on the expression of genes that quench the damaging effects of reactive oxygen species. However, it turns out that the key to PGC-1α’s ability to induce clearance of mutant huntingtin protein aggregates is its capacity to switch on the expression of TFEB, a master regulatory transcription factor that activates genes in the autophagy-lysosome pathway of protein turnover. Regulation of TFEB by PGC-1α underscores the importance of maintaining mitochondrial quality control under conditions of accelerated mitochondrial biogenesis and increased ATP generation. As altered energy production and impaired protein quality control are key features of other neurodegenerative diseases like Parkinson’s disease, the new findings suggest that PGC-1α and TFEB may be useful therapeutic targets not only for HD but for other neurodegenerative disorders as well.