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Cited by 197Nerve injury and regenerationAxon Guidance and Neuronal SignalingGlaucoma and retinal disorders

ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS

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Koch, J C, Tönges, L, Barski, E, Michel, U, Bähr, M, Lingor, P·2014·Cell Death & Disease
DOI 10.1038/cddis.2014.191PMC PMC4047920
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Abstract

The Rho/ROCK/LIMK pathway is central for the mediation of repulsive environmental signals in the central nervous system. Several studies using pharmacological Rho-associated protein kinase (ROCK) inhibitors have shown positive effects on neurite regeneration and suggest additional pro-survival effects in neurons. However, as none of these drugs is completely target specific, it remains unclear how these effects are mediated and whether ROCK is really the most relevant target of the pathway. To answer these questions, we generated adeno-associated viral vectors to specifically downregulate ROCK2 and LIM domain kinase (LIMK)-1 in rat retinal ganglion cells (RGCs) in vitro and in vivo. We show here that specific knockdown of ROCK2 and LIMK1 equally enhanced neurite outgrowth of RGCs on inhibitory substrates and both induced substantial neuronal regeneration over distances of more than 5 mm after rat optic nerve crush (ONC) in vivo. However, only knockdown of ROCK2 but not LIMK1 increased survival of RGCs after optic nerve axotomy. Moreover, knockdown of ROCK2 attenuated axonal degeneration of the proximal axon after ONC assessed by in vivo live imaging. Mechanistically, we demonstrate here that knockdown of ROCK2 resulted in decreased intraneuronal activity of calpain and caspase 3, whereas levels of pAkt and collapsin response mediator protein 2 and autophagic flux were increased. Taken together, our data characterize ROCK2 as a specific therapeutic target in neurodegenerative diseases and demonstrate new downstream effects of ROCK2 including axonal degeneration, apoptosis and autophagy.

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  • Inhibition of ROCK or direct downregulation of ROCK expression results in activation of both autophagy and the UPS, indicating that RhoA/ROCK signaling negatively regulates degradation pathways.

    “Several studies have shown that inhibition of ROCK or direct downregulation of ROCK expression results in the activation of both autophagy and the UPS, indicating that RhoA/ROCK signaling negatively regulates the degradation pathways [142,143,144,145,146].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [144]

    The Results section reports increased autophagic flux in retinal ganglion cells after ROCK2-shRNA downregulation, supporting the autophagy part of the claim. It does not report activation of the ubiquitin–proteasome system (UPS); its reference to ubiquitinated substrates explains the role of p62 in assessing autophagy, not UPS activity. The Discussion also notes a study in which ROCK inhibition impaired a starvation-mediated autophagic response, so the claim is too broad about ROCK inhibition generally. No page number is available in our copy. (LLM, conf=0.89)

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Authors
Koch, J. C., Tönges, L., Barski, E., Michel, U., Bähr, M., & Lingor, P.
Affiliations
Universitätsmedizin Göttingen (DE)
Corresponding author
Koch, J C
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2014-05-15
Volume
5
Issue
5
Pages
e1225-e1225
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2014.191
PMC
PMC4047920
OpenAlex
W2070218098
Cited by
197
References
3
Citations by year
2026: 5 · 2025: 15 · 2024: 17 · 2023: 11 · 2022: 16 · 2021: 27 · 2020: 20 · 2019: 15 · 2018: 14 · 2017: 13 · 2016: 18 · 2015: 21 · 2014: 5
FWCI
7.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by-nc-sa)
  • GRO (submittedVersion, cc-by-nc-sa)
Funders
Deutsche Forschungsgemeinschaft (1308/3-1, LI 1308/3-1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
Keywords
ROCK2, axonal degeneration, axon regeneration, neuronal cell death, retinal ganglion cells, optic nerve crush, axotomy, neurite outgrowth, calpain, caspase-3, autophagy, CRMP2, Akt signaling, neurodegenerative diseases, adeno-associated virus vectors, gene knockdown
MeSH terms
Dependovirus, Animals, Autophagy, Axons, Calpain, Cells, Cultured, Disease Models, Animal, Female, Genetic Vectors, Nerve Crush, Nerve Degeneration, Nerve Regeneration, Nerve Tissue Proteins, Optic Nerve, Phosphorylation, Retinal Ganglion Cells, Time Factors, Transfection, Signal Transduction, Neurites, Cell Death, Rats, Wistar, Apoptosis, Gene Transfer Techniques, Optic Nerve Injuries, RNA Interference, Intercellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Rats, Caspase 3, rho-Associated Kinases, Lim Kinases, Gene Knockdown Techniques

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