Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington's disease.

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 beta-catenin. ...
Huntingtin associates with the beta-catenin destruction complex that ensures its equilibrated degradation. The binding of beta-catenin to the destruction complex is altered in HD, leading to the toxic stabilization of beta-catenin. As a consequence, the beta-transducin repeat-containing protein (beta-TrCP) rescues polyglutamine (polyQ)-huntingtin-induced toxicity in striatal neurons and in a Drosophila model of HD, through the specific degradation of beta-catenin. Finally, the non-steroidal anti-inflammatory drug indomethacin that decreases beta-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 beta-catenin homeostasis in HD is of therapeutic interest.
Mesh Terms:
Aged, Aged, 80 and over, Animals, Anti-Inflammatory Agents, Non-Steroidal, Armadillo Domain Proteins, Cell Cycle Proteins, Cells, Cultured, Drosophila Proteins, Drosophila melanogaster, Humans, Huntington Disease, Indomethacin, Mice, Mice, Knockout, Middle Aged, Mutation, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Peptides, RNA Interference, Transcription Factors, Ubiquitin-Protein Ligases, beta Catenin
EMBO J.
Date: Jul. 21, 2010
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