PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function

Sci Transl Med. 2012 Jul 11;4(142):142ra97. doi: 10.1126/scitranslmed.3003799.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Huntington Disease / complications
  • Huntington Disease / pathology*
  • Huntington Disease / prevention & control*
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Nerve Degeneration / complications
  • Nerve Degeneration / pathology
  • Oxidative Stress / drug effects*
  • Peptides / toxicity*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phenotype
  • Protein Structure, Quaternary
  • Reactive Oxygen Species / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Transcriptional Activation / genetics
  • Trinucleotide Repeat Expansion / genetics


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Peptides
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Tcfeb protein, mouse
  • Trans-Activators
  • Transcription Factors
  • polyglutamine