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- Title
Mutant huntingtin-impaired degradation of β-catenin causes neurotoxicity in Huntington's disease.
- Authors
Godin, Juliette D.; Poizat, Ghislaine; Hickey, Miriam A.; Maschat, Florence; Humbert, Sandrine
- Abstract
Huntington's disease (HD) is a fatal neurodegenerative disorder causing selective neuronal death in the brain. Dysfunction of the ubiquitin–proteasome system may contribute to the disease; however, the exact mechanisms are still unknown. We report here a new pathological mechanism by which mutant huntingtin specifically interferes with the degradation of β-catenin. Huntingtin associates with the β-catenin destruction complex that ensures its equilibrated degradation. The binding of β-catenin to the destruction complex is altered in HD, leading to the toxic stabilization of β-catenin. As a consequence, the β-transducin repeat-containing protein (β-TrCP) rescues polyglutamine (polyQ)-huntingtin-induced toxicity in striatal neurons and in a Drosophila model of HD, through the specific degradation of β-catenin. Finally, the non-steroidal anti-inflammatory drug indomethacin that decreases β-catenin levels has a neuroprotective effect in a neuronal model of HD and in Drosophila and increases the lifespan of HD flies. We thus suggest that restoring β-catenin homeostasis in HD is of therapeutic interest.
- Subjects
HUNTINGTON disease; NEUROTOXICOLOGY; NEURODEGENERATION; UBIQUITIN; PROTEINS
- Publication
EMBO Journal, 2010, Vol 29, Issue 14, p2433
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/emboj.2010.117