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Cited by 142Autophagy in Disease and TherapyParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway

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Moskal, Natalia, Riccio, Victoria, Bashkurov, Mikhail, Taddese, Rediet, Datti, Alessandro, Lewis, Peter N., Angus McQuibban, G.·2020·Nature Communications
DOI 10.1038/s41467-019-13781-3PMC PMC6941965
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Abstract

The accumulation of damaged mitochondria causes the death of dopaminergic neurons. The Parkin-mediated mitophagy pathway functions to remove these mitochondria from cells. Targeting this pathway represents a therapeutic strategy for several neurodegenerative diseases, most notably Parkinson’s disease. We describe a discovery pipeline to identify small molecules that increase Parkin recruitment to damaged mitochondria and ensuing mitophagy. We show that ROCK inhibitors promote the activity of this pathway by increasing the recruitment of HK2, a positive regulator of Parkin, to mitochondria. This leads to the increased targeting of mitochondria to lysosomes and removal of damaged mitochondria from cells. Furthermore, ROCK inhibitors demonstrate neuroprotective effects in flies subjected to paraquat, a parkinsonian toxin that induces mitochondrial damage. Importantly, parkin and rok are required for these effects, revealing a signaling axis which controls Parkin-mediated mitophagy that may be exploited for the development of Parkinson’s disease therapeutics.

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  • The ROCK inhibitor SR3677 was the most efficient at increasing parkin recruitment, and its neuroprotective effect was verified in vivo in a fly PD model subjected to paraquat.

    “The inhibitor SR3677 was the most efficient, and its neuroprotective effect was verified in vivo in a fly PD model subjected to paraquat, a parkinsonian toxin that induces mitochondrial damage [139].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [139]

    The Results section on in vivo effects reports that SR3677 improved survival and climbing ability in paraquat-treated flies. But the Results section on Parkin recruitment says SR3677 ranked lower than other ROCK inhibitors in the screen; it does not support calling SR3677 the most efficient at increasing recruitment. Page numbers were not supplied in our copy. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Akt-mediated activation of HK2 is required for its translocation to damaged mitochondria and subsequent recruitment of Parkin to initiate mitophagy.

    “Furthermore, it was recently suggested that ROCK inhibits Parkin-mediated mitophagy via PTEN antagonization of the PI3K/Akt pathway [139] as Akt-mediated activation of hexokinase 2 (HK2) is required for its translocation to damaged mitochondria and subsequent recruitment of Parkin to initiate mitophagy [139,140] (Figure 3).”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [139]

  • A high-throughput screen of approximately 3000 compounds in HEK293 cells identified several ROCK inhibitors that increased the recruitment of parkin to damaged mitochondria, leading to increased targeting of mitochondria to lysosomes and removal of damaged mitochondria.

    “A recent high-throughput screen of ~3000 compounds in HEK293 cells identified several ROCK inhibitors that increased the recruitment of parkin to damaged mitochondria, leading to increased targeting of mitochondria to lysosomes and removal of damaged mitochondria from the cells.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [139]

  • ROCK inhibits Parkin-mediated mitophagy via PTEN antagonization of the PI3K/Akt pathway.

    “Furthermore, it was recently suggested that ROCK inhibits Parkin-mediated mitophagy via PTEN antagonization of the PI3K/Akt pathway [139] as Akt-mediated activation of hexokinase 2 (HK2) is required for its translocation to damaged mitochondria and subsequent recruitment of Parkin to initiate mitophagy [139,140] (Figure 3).”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [139]

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Cited by

Sorted by citations

Authors
Moskal, N., Riccio, V., Bashkurov, M., Taddese, R., Datti, A., Lewis, P. N., & Angus McQuibban, G.
Affiliations
  • University of Toronto (CA)
  • Mount Sinai Hospital (CA)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-01-03
Volume
11
Issue
1
Pages
88-88
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-13781-3
PMC
PMC6941965
OpenAlex
W2997404986
Cited by
142
References
6
Citations by year
2026: 14 · 2025: 33 · 2024: 22 · 2023: 23 · 2022: 21 · 2021: 18 · 2020: 10 · 2019: 1
FWCI
12.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
ROCK inhibitor, Parkin, mitophagy, HK2, Parkinson's disease, dopaminergic neurons, mitochondrial damage, paraquat, neuroprotection, small molecule drug discovery, lysosomal targeting, neurodegenerative disease therapeutics
MeSH terms
Animals, Diptera, Enzyme Inhibitors, Hexokinase, Humans, Male, Mitochondria, Signal Transduction, Neuroprotective Agents, Ubiquitin-Protein Ligases, Cell Line, Tumor, rho-Associated Kinases, Mitophagy

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