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Author Notes:

Correspondence should be addressed to Dr. Jeremy H. Herskowitz, Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, 1825 University Bouldvard, Birmingham, AL 35294. E-mail: jhersko@uab.edu.

A.E.A., N.C.R., and J.H.H. designed research; E.G.G., B.W.H., A.E.A., N.C.R., and J.H.H. performed research; M.G. and Y.F. contributed unpublished reagents/analytic tools; E.G.G., B.W.H., A.E.A., Y.F., N.C.R., and J.H.H. analyzed data; J.H.H. wrote the paper.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by National Institutes of Health/National Institute on Aging Grant 5R00AG043552-04 (J.H.H.), National Institute of Neurological Disorders and Stroke Neuroscience Core Facilities Grant NS055077, Alzheimer’s Disease Research Center Grant AG025688 at Emory University, and Alzheimer’s Association New Investigator Research Grant 2015-NIRG-339422 (J.H.H.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • autophagy
  • Drosophila
  • Rho kinase
  • ROCK
  • tau
  • tauopathy
  • AMYLOID-BETA PRODUCTION
  • DROSOPHILA-MELANOGASTER
  • ALZHEIMERS-DISEASE
  • MAMMALIAN TARGET
  • TAU-PROTEIN
  • NEUROFIBRILLARY PATHOLOGY
  • RAPAMYCIN MTOR
  • ROCK-II
  • DEGRADATION
  • HAPLOTYPE

Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration

Tools:

Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 36, Number 4

Publisher:

, Pages 1316-1323

Type of Work:

Article | Final Publisher PDF

Abstract:

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets with clinically available drugs are lacking. Here, we report that protein levels of the Rho-associated protein kinases (ROCK1 and ROCK2), p70 S6 kinase (S6K), and mammalian target of rapamycin (mTOR) were increased in PSP and CBD brains. RNAi depletion of ROCK1 or ROCK2 reduced taumRNA and protein level in human neuroblastoma cells. However, additional phenotypes were observed under ROCK2 knockdown, including decreased S6K and phosphorylated mTOR levels. Pharmacologic inhibition of Rho kinases in neurons diminished detergent-soluble and -insoluble tau through a combination of autophagy enhancement and tau mRNA reduction. Fasudil, a clinically approved ROCK inhibitor, suppressed rough eye phenotype and mitigated pathogenic tau levels by inducing autophagic pathways in a Drosophila model of tauopathy. Collectively, these findings highlight the Rho kinases as rational therapeutic targets to combat tau accumulation in PSP and CBD.

Copyright information:

©2016 the authors

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