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Gentry EG, Henderson BW, Arrant AE, Gearing M, Feng Y, Riddle NC, Herskowitz JH. Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration. J Neurosci. 2016 Jan 27;36(4):1316-23. PubMed.
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Gentry et al.’s discovery that Rho-associated protein kinases (ROCK1 and ROCK2) associate with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) adds to the growing list of neurodegenerative diseases in which ROCK hyperactivity has been implicated as a contributor to the neurodegenerative process. Specifically, the authors demonstrate an upregulation of the ROCK2–S6K–pmTOR axis in CBD and PSP and propose a mechanism by which autophagy is inhibited as a result of S6K-mediated pmTOR activation, consequently leading to tau accumulation. In support of their hypothesis, knockdown of ROCK2, or pharmacological inhibition with a selective ROCK2 inhibitor, reduced levels of tau in neuronal cells and ameliorated tau pathology in a Drosophila model.
ROCK kinases are at the center of a number of molecular networks and several studies suggest ROCK inhibition benefits animal models of various neurodegenerative diseases, including Parkinson’s, Alzheimer’s, Huntington’s disease, multiple sclerosis, spinal muscular atrophy, and ALS. It is important to note that a number of different pathways by which ROCK inhibition may have beneficial effects were proposed in these studies, including direct and indirect effects on axonal regeneration and outgrowth, neuronal survival, change in microglial activation status, and pathological protein aggregation.
As such, ROCK presents an interesting molecular target for the treatment of diseases such as AD, where ROCK inhibition appears to have beneficial effects on both Aβ and tau accumulation, suggesting it may have potential for other tauopathies, including forms of frontotemporal dementia; the results presented by Gentry and colleagues speak to this possibility. However, poor isoform selectivity and potential inhibition of peripheral targets may cause detrimental side effects that prohibit the systemic application of small molecule inhibitors of ROCK in these chronic diseases. Human experience with ROCK inhibitors such as fasudil, which is approved in Japan for the treatment of post-subarachnoid hemorrhage vasospasm, and experimental ROCK inhibitors currently in clinical trials in various indications such as glaucoma, pulmonary artery hypertension, Raynaud’s syndrome, and malignant diseases, is still limited and virtually non-existent in the case of neurodegenerative diseases. However, accumulating data from in vitro and in vivo studies, such as this one published by Gentry et al., highlight ROCK inhibition as a worthwhile target for drug discovery and future clinical development in neurodegenerative diseases.
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