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 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aged
-
Aged, 80 and over
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / metabolism
-
Armadillo Domain Proteins / genetics
-
Armadillo Domain Proteins / metabolism*
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cells, Cultured
-
Drosophila Proteins / genetics
-
Drosophila Proteins / metabolism*
-
Drosophila melanogaster / anatomy & histology
-
Drosophila melanogaster / genetics
-
Drosophila melanogaster / metabolism
-
Humans
-
Huntingtin Protein
-
Huntington Disease / metabolism*
-
Huntington Disease / pathology*
-
Huntington Disease / physiopathology
-
Indomethacin / metabolism
-
Mice
-
Mice, Knockout
-
Middle Aged
-
Mutation
-
Nerve Tissue Proteins* / genetics
-
Nerve Tissue Proteins* / metabolism
-
Neurons / cytology
-
Neurons / metabolism
-
Nuclear Proteins* / genetics
-
Nuclear Proteins* / metabolism
-
Peptides / metabolism
-
RNA Interference
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism
-
beta Catenin / metabolism*
Substances
-
ARM protein, Drosophila
-
Anti-Inflammatory Agents, Non-Steroidal
-
Armadillo Domain Proteins
-
Cell Cycle Proteins
-
Drosophila Proteins
-
HTT protein, human
-
Htt protein, mouse
-
Huntingtin Protein
-
Nerve Tissue Proteins
-
Nuclear Proteins
-
Peptides
-
Transcription Factors
-
beta Catenin
-
slmb protein, Drosophila
-
polyglutamine
-
Ubiquitin-Protein Ligases
-
Indomethacin