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.

Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

“…Therefore, targeted therapies for HD could inhibit mHtt aggregation or prevent cellular damage resulting from mHtt cytotoxicity. Approaches to decrease mHtt protein levels include allele-specific silencing expression of the mutant HTT gene (27), as well as the activation of autophagy (28) and the ubiquitin-proteasome system (29). In addition, inhibition of mHtt aggregation by elevating molecular chaperones, as well as antiaggregation drugs, is beneficial for the early stages of HD pathogenesis (13,30).…”

Distinct Distribution and Localization of Rho-kinase in Mouse Epithelial, Muscle and Neural Tissues

“…9W and X). Profilin is a major actin-regulatory protein in the excitatory postsynapse (Ackermann and Matus, 2003) and a substrate of Rho-kinase (Shao et al, 2008;Bauer et al, 2009). Active RhoA directly interacts with N-methyl-D-aspartate-(NMDA) type receptors and recruits the Rho-kinase/profilin complex to the PSD and then activates it, thereby stabilizing actin filaments (Schubert et al, 2006).…”

Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

“…Angiogenesis is the formation of new capillary blood vessels from endothelial or stem cells, and is essential during wound healing, embryonic development and tumorigenesis (1). Angiogenesis is intricately regulated by a number of factors, including the extracellular matrix, growth factors, membranebound proteinases and integrins which induce cytoskeleton rearrangement and delicately orchestrate the various steps of angiogenesis, including endothelial cell (EC) proliferation, branching and sprouting and lumen formation (2).…”