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PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function.
- Source :
-
Science translational medicine [Sci Transl Med] 2012 Jul 11; Vol. 4 (142), pp. 142ra97. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics
Huntington Disease complications
Mice
Mice, Transgenic
Mitochondria drug effects
Mitochondria metabolism
Nerve Degeneration complications
Nerve Degeneration pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phenotype
Protein Structure, Quaternary
Reactive Oxygen Species metabolism
Transcription Factors
Transcriptional Activation genetics
Trinucleotide Repeat Expansion genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Huntington Disease pathology
Huntington Disease prevention & control
Oxidative Stress drug effects
Peptides toxicity
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 4
- Issue :
- 142
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 22786682
- Full Text :
- https://doi.org/10.1126/scitranslmed.3003799