Enhanced degradation of mutant huntingtin by rho kinase inhibition is mediated through activation of proteasome and macroautophagy.
Enhancing the degradation of mutant protein is one of the most investigated approaches in experimental therapy of the polyglutamine-related disorders such as Huntington disease (HD). Inhibition of rho-associated kinases (ROCKs) reduced the aggregation and levels of mutant huntingtin in cellular models of HD via activation of the ubiquitin proteasome system (UPS) and macroautophagy. This unique effect makes the Rho/ROCK pathway and its downstream effectors attractive therapeutic targets for polyglutamine-related diseases.
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako-shi, Japan.
Peter O
PO
Bauer
Nobuyuki
N
Nukina
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000577:Amides; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases; D046988:Proteasome Endopeptidase Complex