title: Inhibition of Rho kinases enhances the degradation of mutant huntingtin.
abstract: Huntington disease (HD) is a fatal hereditary neurodegenerative disease caused by an expansion of the polyglutamine (polyQ) stretch in huntingtin (htt). Whereas the pathological significance of the expanded polyQ has been clearly established and a tremendous effort to develop therapeutic tools for HD has been exerted, there is yet no effective cure. Whereas many molecules able to reduce the polyQ accumulation and aggregation have been identified, including several Rho kinase (ROCK) inhibitors, it remains very important to determine the mechanism of action of the potential drugs. ROCK inhibitors, including Y-27632 were reported to decrease aggregation of htt and androgen receptor (AR) through ROCK1 and protein kinase C-related protein kinase-2 (PRK-2). A downstream effector of ROCK1, actin-binding factor profilin, was shown to inhibit the mutant htt aggregation but not AR by direct interaction. We found that the anti-aggregation effect of ROCK inhibitors was not limited to the mutant htt and AR and that Y-27632 was also able to reduce the aggregation of ataxin-3 and atrophin-1 with expanded polyQ. These results suggested that in addition to the mechanism reported for htt and AR, there might also be other common mediators involved in the reduced aggregation of different polyQ proteins. In this study, we show that Y-27632 not only reduced the mutant htt aggregation by enhancing its degradation, but surprisingly was able to activate the main cellular degradation pathways, proteasome, and macroautophagy. We also show that this unique effect was mediated by ROCK1 and ROCK2.
authors.affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Peter O
authors.initials: PO
authors.lastname: Bauer
authors.forename: Hon Kit
authors.initials: HK
authors.lastname: Wong
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oyama
authors.forename: Anand
authors.initials: A
authors.lastname: Goswami
authors.forename: Misako
authors.initials: M
authors.lastname: Okuno
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.forename: Haruko
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D000067699:Ataxin-3; D001343:Autophagy; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D051304:Profilins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C410798:AR protein, human; D000577:Amides; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C495738:PFN1 protein, human; D010455:Peptides; D051304:Profilins; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012097:Repressor Proteins; C095278:atrophin-1; C485184:enhanced green fluorescent protein; C108830:Y 27632; D049452:Green Fluorescent Proteins; C097188:polyglutamine; C061570:protein kinase N; D054460:rho-Associated Kinases; D011493:Protein Kinase C; C092341:ATXN3 protein, human; D000067699:Ataxin-3