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Cited by 179Traumatic Brain Injury and Neurovascular DisturbancesProtein Kinase Regulation and GTPase SignalingTraumatic Brain Injury Research

RhoA-ROCK Signaling as a Therapeutic Target in Traumatic Brain Injury

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Mulherkar, Shalaka, Tolias, Kimberley F.·2020·Cells
DOI 10.3390/cells9010245PMC PMC7016605
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Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBIs, which range in severity from mild to severe, occur when a traumatic event, such as a fall, a traffic accident, or a blow, causes the brain to move rapidly within the skull, resulting in damage. Long-term consequences of TBI can include motor and cognitive deficits and emotional disturbances that result in a reduced quality of life and work productivity. Recovery from TBI can be challenging due to a lack of effective treatment options for repairing TBI-induced neural damage and alleviating functional impairments. Central nervous system (CNS) injury and disease are known to induce the activation of the small GTPase RhoA and its downstream effector Rho kinase (ROCK). Activation of this signaling pathway promotes cell death and the retraction and loss of neural processes and synapses, which mediate information flow and storage in the brain. Thus, inhibiting RhoA-ROCK signaling has emerged as a promising approach for treating CNS disorders. In this review, we discuss targeting the RhoA-ROCK pathway as a therapeutic strategy for treating TBI and summarize the recent advances in the development of RhoA-ROCK inhibitors.

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  • RhoA and Rac/Cdc42 typically exhibit an antagonistic relationship to regulate neuronal morphology.

    “Hence, RhoA and Rac/Cdc42 typically exhibit an antagonistic relationship to regulate neuronal morphology [1,7].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [7]

    Section 3 says Rac1 promotes axon and dendrite growth and branching and dendritic-spine maintenance, whereas RhoA typically inhibits those processes. This supports opposing effects on neuronal morphology, but the paper does not establish the same relationship for Cdc42; Section 2 only identifies Cdc42 as a Rho-family GTPase involved in morphogenesis. No page number is available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ROCK phosphorylates the myosin light chain subunit of myosin IIb, leading to actomyosin assembly and contractility, both through direct interaction and indirectly by ROCK-mediated inhibition of MLCP through phosphorylation of MYPT1.

    “ROCK also phosphorylates the myosin light chain (MLC) subunit of the actin-based motor protein myosin IIb, leading to actomyosin assembly and contractility. This occurs both through a direct interaction and indirectly by ROCK-mediated inhibition of myosin light chain phosphatase (MLCP) through phosphorylation of its myosin phosphatase-targeting subunit 1 (MYPT1) [7].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [7]

    Section 2, “Rho GTPase Signaling” (page not provided), says ROCK increases MLC phosphorylation and actomyosin contractile force, both directly and through phosphorylation and inhibition of myosin phosphatase. It identifies the motor protein as myosin II, not specifically myosin IIb, and does not identify MYPT1 as the phosphorylated phosphatase subunit or explicitly describe actomyosin assembly. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.

    “Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [7]

    Section 3 implicates dysregulated Rho GTPase signaling in Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. It does not name Huntington’s disease, and its disease-specific statement concerns Rho GTPases generally rather than RhoA specifically; the following RhoA discussion concerns CNS injury. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Many neuronal studies support the general model that Rac and Cdc42 stimulate neuronal growth cone dynamics, dendritic spine formation, and axonal extension and guidance, while RhoA inhibits these processes and causes axonal and dendritic retraction and spine and synapse loss.

    “Many neuronal studies support the general model that Rac and Cdc42 stimulate these processes, while RhoA inhibits them and causes axonal and dendritic retraction and spine and synapse loss.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [7]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Dysregulation of Rho GTPases has been studied in relation to cancer progression, but accumulating evidence supports a role in traumatic brain injury and neurodegenerative diseases.

    “Dysregulation of Rho GTPases has been studied in relation to cancer progression for a number of years [3], but accumulating evidence supports a role in traumatic brain injury and neurodegenerative diseases as well [4,5,6,7].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [7]

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Cited by

Sorted by citations

Authors
Mulherkar, S., & Tolias, K. F.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Tolias, Kimberley F.
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2020-01-18
Volume
9
Issue
1
Pages
245
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells9010245
PMC
PMC7016605
OpenAlex
W2999339913
Cited by
179
References
5
Citations by year
2026: 22 · 2025: 27 · 2024: 40 · 2023: 28 · 2022: 35 · 2021: 20 · 2020: 7
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Defense (W81XWH0820148)
  • TIRR Foundation - Mission Connect (x)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Keywords
traumatic brain injury, RhoA/ROCK signaling, Rho kinase, RhoA, small GTPases, therapeutic target, neuronal cell death, synaptic loss, central nervous system injury, neuroprotection
MeSH terms
Brain Injuries, Traumatic, Animals, Disease Models, Animal, Humans, Signal Transduction, rho GTP-Binding Proteins, rho-Associated Kinases, Molecular Targeted Therapy

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