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Cited by 239Protein Kinase Regulation and GTPase SignalingAlzheimer's disease research and treatmentsParkinson's Disease Mechanisms and Treatments

ROCK inhibition in models of neurodegeneration and its potential for clinical translation

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Koch, Jan Christoph, Tatenhorst, Lars, Roser, Anna-Elisa, Saal, Kim-Ann, Tönges, Lars, Lingor, Paul·2018·Pharmacology & Therapeutics
DOI 10.1016/j.pharmthera.2018.03.008
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Abstract

Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders.

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  • In most cell types, the effect of RhoA on cytoskeletal dynamics is primarily mediated by its activation of ROCK, which via phosphorylation and activation of LIMK increases the phosphorylation and inactivation of cofilin 1 to stabilize actin filaments, leading to reduced actin turnover and inhibition of neurite outgrowth.

    “In most cell types, the effect of RhoA on cytoskeletal dynamics is primarily mediated by its activation of ROCK, which via phosphorylation and activation of LIM kinase (LIMK) increases the phosphorylation and inactivation of cofilin 1 (an actin-depolymerizing and severing factor) to stabilize actin filaments. This leads to reduced actin turnover and inhibition of neurite outgrowth [118].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [118]

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  • In astrocytes, RhoA/ROCK signaling plays a major role in determining astrocyte morphology and reactive state.

    “In astrocytes, RhoA/ROCK signaling plays a major role in determining astrocyte morphology and reactive state [118,160,161], and ROCK inhibition reduces reactive gliosis and increases astrocytic expression of prosurvival genes [162,163].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [118]

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Cited by

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Authors
Koch, J. C., Tatenhorst, L., Roser, A.-E., Saal, K.-A., Tönges, L., & Lingor, P.
Affiliations
  • Universitätsmedizin Göttingen (DE)
  • Ruhr University Bochum (DE)
Corresponding author
Lingor, Paul
ORCID
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2018-09
Volume
189
Pages
1-21
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/j.pharmthera.2018.03.008
OpenAlex
W2795818410
Cited by
239
References
7
Citations by year
2026: 17 · 2025: 37 · 2024: 37 · 2023: 18 · 2022: 28 · 2021: 37 · 2020: 44 · 2019: 14 · 2018: 6
FWCI
2.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacology & Therapeutics (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
Rho kinase, ROCK inhibition, neurodegeneration, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, disease-modifying therapy, axonal degeneration, autophagy, synaptic function, glial function, ROCK inhibitor, animal models of neurodegeneration, therapeutic target
MeSH terms
Animals, Disease Models, Animal, Humans, Neurons, Neurodegenerative Diseases, Protein Kinase Inhibitors, rho-Associated Kinases

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