| First Author | Tsunemi T | Year | 2012 |
| Journal | Sci Transl Med | Volume | 4 |
| Issue | 142 | Pages | 142ra97 |
| PubMed ID | 22786682 | Mgi Jnum | J:186693 |
| Mgi Id | MGI:5432945 | Doi | 10.1126/scitranslmed.3003799 |
| Citation | Tsunemi T, et al. (2012) PGC-1alpha Rescues Huntington's Disease Proteotoxicity by Preventing Oxidative Stress and Promoting TFEB Function. Sci Transl Med 4(142):142ra97 |
| abstractText | 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 (PPARgamma) coactivator 1alpha (PGC-1alpha), a regulator of mitochondrial biogenesis and oxidative stress. We tested whether restoration of PGC-1alpha could ameliorate the symptoms of HD in a mouse model. We found that PGC-1alpha induction virtually eliminated htt protein aggregation and ameliorated HD neurodegeneration in part by attenuating oxidative stress. PGC-1alpha 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-1alpha upstream of TFEB and identifying these two molecules as important therapeutic targets in HD and potentially other neurodegenerative disorders caused by protein misfolding. |
