title: Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration.
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 tau mRNA 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.
  
  
  CONCLUSIONS
  Studies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) suggest that mitigating pathogenic tau levels is a rational strategy for tauopathy treatment. In this report, the Rho-associated protein kinases (ROCK1 and ROCK2) are identified as novel drug targets for PSP and CBD. We show that elevated insoluble tau levels are associated with increased ROCK1 and ROCK2 in PSP and CBD brains, whereas experiments in cellular and animal models identify pharmacologic inhibition of ROCKs as a mechanism-based approach to reduce tau levels. Our study correlates bona fide changes in PSP and CBD brains with cellular models, identifies drug targets, and tests the therapeutic in vivo.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics and Departments of Neurology.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Gentry
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics and Departments of Neurology.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Henderson
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics and Departments of Neurology.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arrant
authors.affiliation: Departments of Pathology and Laboratory Medicine, and Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, and.
authors.forename: Marla
authors.identifier: http://orcid.org/0000-0002-1959-7412
authors.initials: M
authors.lastname: Gearing
authors.affiliation: Medicinal Chemistry, Translational Research Institute, Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Nicole C
authors.identifier: http://orcid.org/0000-0003-1827-9145
authors.initials: NC
authors.lastname: Riddle
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics and Departments of Neurology, Neurobiology, and jhersko@uab.edu.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Herskowitz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D030801:Animals, Genetically Modified; D001480:Basal Ganglia Diseases / Q000473:pathology*; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D004330:Drosophila; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013494:Supranuclear Palsy, Progressive / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; C546842:MTOR protein, human; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D054460:rho-Associated Kinases
keywords: Drosophila; ROCK; Rho kinase; autophagy; tau; tauopathy
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