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Cited by 96Parkinson's Disease Mechanisms and TreatmentsMitochondrial Function and PathologyNuclear Receptors and Signaling

ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson’s disease

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Zhang, Qian, Hu, Changpeng, Huang, Jingbin, Liu, Wuyi, Lai, Wenjing, Leng, Faning, Tang, Qin, Liu, Yali +5 more·2019·Experimental & Molecular Medicine
DOI 10.1038/s12276-019-0318-zPMC PMC6802738
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Abstract

Dopamine deficiency is mainly caused by apoptosis of dopaminergic nerve cells in the substantia nigra of the midbrain and the striatum and is an important pathologic basis of Parkinson’s disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays a crucial role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study showed that Drp1 knockdown inhibited aberrant mitochondrial fission and apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cells by suppressing Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms in a PD mouse model by inhibiting Drp1-mediated aberrant mitochondrial fission and apoptosis. Collectively, our findings suggest an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via the activation of Drp1-induced aberrant mitochondrial fission.

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  • In MPTP-treated PC12 cells and an MPTP mouse model, ROCK inhibition using Y27632 rescues Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic neurons.

    “In MPTP-treated PC12 cells and a MPTP mouse model, ROCK inhibition using Y27632 rescued Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic neurons [132].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [132]

    The Results (Fig. 4; page not specified) report that Y-27632 attenuated Drp1-dependent mitochondrial fission and apoptosis in PC12 cells, but those cells were treated with MPP+, not MPTP. The Results (Fig. 5; page not specified) support the corresponding finding in MPTP-treated mice, including protection of dopaminergic nerve cells. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Activated ROCK promotes mitochondrial fission and subsequent apoptosis in dopaminergic neurons via activation of Drp1.

    “Activated ROCK was found to promote mitochondrial fission and subsequent apoptosis in dopaminergic neurons via the activation of dynamin-related protein 1 (Drp1) [132].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [132]

  • In dopaminergic neurons, ROCK-mediated dephosphorylation of Drp1 was reported to induce mitochondrial fission.

    “It seems that ROCK can directly phosphorylate Drp1 to increase the fission activity of Drp1 in cardiomyocytes and podocytes [133,134], while in dopaminergic neurons, a ROCK-mediated dephosphorylation of Drp1 was reported to induce mitochondrial fission [132].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [132]

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Cited by

Sorted by citations

Authors
Zhang, Q., Hu, C., Huang, J., Liu, W., Lai, W., Leng, F., Tang, Q., Liu, Y., Wang, Q., Zhou, M., Sheng, F., Li, G., & Zhang, R.
Affiliations
Army Medical University (CN)
Corresponding author
  • Li, Guobing
  • Zhang, Rong
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-10
Volume
51
Issue
10
Pages
1-13
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-019-0318-z
PMC
PMC6802738
OpenAlex
W2977503598
Cited by
96
References
3
Citations by year
2026: 14 · 2025: 14 · 2024: 11 · 2023: 10 · 2022: 17 · 2021: 18 · 2020: 12
FWCI
7.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81801273, 81874357)
  • Natural Science Foundation of Chongqing (cstc2018jcyjAX0183)
  • Clinical Research Projects of second Affiliated Hospital, Army Medical University
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
ROCK1, Drp1, mitochondrial fission, dopaminergic neuron apoptosis, Parkinson's disease, MPP+, Y-27632, substantia nigra, dopamine deficiency
MeSH terms
Amides, Animals, Dopamine, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Mitochondria, Parkinson Disease, Secondary, Pyridines, Substantia Nigra, Signal Transduction, 1-Methyl-4-phenylpyridinium, PC12 Cells, Apoptosis, Mice, Knockout, Oxidative Stress, Dynamins, Mice, Rats, Membrane Potential, Mitochondrial, rho-Associated Kinases, Dopaminergic Neurons, Mitochondrial Dynamics

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