PMID- 26818518
OWN - NLM
STAT- MEDLINE
DCOM- 20160601
LR  - 20220309
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 36
IP  - 4
DP  - 2016 Jan 27
TI  - Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and 
      Corticobasal Degeneration.
PG  - 1316-23
LID - 10.1523/JNEUROSCI.2336-15.2016 [doi]
AB  - 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. 
      SIGNIFICANCE STATEMENT: 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.
CI  - Copyright (c) 2016 the authors 0270-6474/16/361316-08$15.00/0.
FAU - Gentry, Erik G
AU  - Gentry EG
AD  - Center for Neurodegeneration and Experimental Therapeutics and Departments of 
      Neurology.
FAU - Henderson, Benjamin W
AU  - Henderson BW
AD  - Center for Neurodegeneration and Experimental Therapeutics and Departments of 
      Neurology.
FAU - Arrant, Andrew E
AU  - Arrant AE
AD  - Center for Neurodegeneration and Experimental Therapeutics and Departments of 
      Neurology.
FAU - Gearing, Marla
AU  - Gearing M
AUID- ORCID: 0000-0002-1959-7412
AD  - Departments of Pathology and Laboratory Medicine, and Neurology, Emory University 
      School of Medicine, Atlanta, Georgia 30322, and.
FAU - Feng, Yangbo
AU  - Feng Y
AD  - Medicinal Chemistry, Translational Research Institute, Scripps Research 
      Institute, Jupiter, Florida 33458.
FAU - Riddle, Nicole C
AU  - Riddle NC
AUID- ORCID: 0000-0003-1827-9145
AD  - Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
FAU - Herskowitz, Jeremy H
AU  - Herskowitz JH
AD  - Center for Neurodegeneration and Experimental Therapeutics and Departments of 
      Neurology, Neurobiology, and jhersko@uab.edu.
LA  - eng
GR  - NS055077/NS/NINDS NIH HHS/United States
GR  - T32 NS061788/NS/NINDS NIH HHS/United States
GR  - AG025688/AG/NIA NIH HHS/United States
GR  - P50 AG025688/AG/NIA NIH HHS/United States
GR  - R00 AG043552/AG/NIA NIH HHS/United States
GR  - 5R00AG043552-04/AG/NIA NIH HHS/United States
GR  - P30 NS055077/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (tau Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (ROCK1 protein, human)
RN  - EC 2.7.11.1 (ROCK2 protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Basal Ganglia Diseases/*pathology
MH  - Brain/*metabolism
MH  - Cell Line, Tumor
MH  - Drosophila
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Gene Expression Regulation, Enzymologic/drug effects/genetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Mutation/genetics
MH  - Nerve Degeneration/pathology
MH  - Neuroblastoma/pathology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Supranuclear Palsy, Progressive/*pathology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - rho-Associated Kinases/*metabolism
MH  - tau Proteins/genetics/metabolism
PMC - PMC4728727
OTO - NOTNLM
OT  - Drosophila
OT  - ROCK
OT  - Rho kinase
OT  - autophagy
OT  - tau
OT  - tauopathy
EDAT- 2016/01/29 06:00
MHDA- 2016/06/02 06:00
PMCR- 2016/07/27
CRDT- 2016/01/29 06:00
PHST- 2016/01/29 06:00 [entrez]
PHST- 2016/01/29 06:00 [pubmed]
PHST- 2016/06/02 06:00 [medline]
PHST- 2016/07/27 00:00 [pmc-release]
AID - 36/4/1316 [pii]
AID - 2336-15 [pii]
AID - 10.1523/JNEUROSCI.2336-15.2016 [doi]
PST - ppublish
SO  - J Neurosci. 2016 Jan 27;36(4):1316-23. doi: 10.1523/JNEUROSCI.2336-15.2016.