Mutant huntingtin‐impaired degradation of β‐catenin causes neurotoxicity in Huntington's disease

JD Godin, G Poizat, MA Hickey, F Maschat… - The EMBO …, 2010 - embopress.org
JD Godin, G Poizat, MA Hickey, F Maschat, S Humbert
The EMBO journal, 2010embopress.org
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 …
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.
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