Fasudil, a Rho kinase inhibitor, promotes the autophagic degradation of A53T α-synuclein by activating the JNK 1/Bcl-2/beclin 1 pathway
Abstract
Accumulation of α-synuclein (α-syn) is pivotally implicated in the pathogenesis of Parkinson׳s disease (PD), and enhancing its clearance might be a promising strategy in PD treatment. It has recently been shown that Rho kinase (ROCK) activation is involved in many neurodegenerative diseases, and some ROCK inhibitors might promote the degradation of abnormal protein aggregates. However, it is not known if fasudil, the only ROCK inhibitor available in clinical setting, could promote the degradation of α-syn, and ameliorate the α-syn induced neurotoxicity. In this regard, we investigated the effect of fasudil on neurite injury caused by A53T α-syn overexpression and the implicated pathway it might mediate. In the current study, we found that under the condition of A53T α-syn overexpression, the neurite outgrowth decreased significantly with the increasing expression of ROCK2. Fasudil, the ROCK inhibitor, ameliorated such neurotoxicity and promoted the clearance of A53T α-syn. Its underlying mechanism was supported by that fasudil could increase the macroautophagy activation via JNK 1 and Bcl-2 phosphorylation and beclin 1/Vps34 complex formation. Taken together, fasudil might be able to provide a novel and promising strategy for PD treatment by enhancing α-syn clearance and activating the JNK 1/Bcl-2/beclin 1 pathway.
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When phosphorylated, Bcl-2 dissociates from Beclin 1, allowing Beclin 1 to complex with Vps34 and initiate autophagosome formation.
“When phosphorylated, Bcl-2 dissociates from Beclin 1, allowing Beclin 1 to complex with Vps34 and initiate autophagosome formation [145].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [145]
ROCK regulates autophagosome formation via PI3K and the JNK/Bcl-2/Beclin 1/Vps34 pathway.
“The exact downstream targets of RhoA/ROCK responsible for this effect are still not fully elucidated, but it has been suggested that ROCK regulates autophagosome formation via PI3K and the JNK/Bcl-2/Beclin 1/Vps34 pathway [145].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [145]
Fasudil-mediated ROCK inhibition induces α-synuclein clearance in A53T-overexpressing SH-SY5Y cells in vitro via activation of autophagy through the JNK/Bcl-2/Beclin 1/Vps34 pathway.
“Fasudil-mediated ROCK inhibition also induced α-synuclein clearance in A53T-overexpressing SH-SY5Y cells in vitro; the underlying mechanism was found to be ROCK inhibition-mediated activation of autophagy via the JNK/Bcl-2/Beclin 1/Vps34 pathway [145].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [145]
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 [145]
In A53T α-syn degradation, inhibition of ROCK in SH-SY5Y cells increased autophagy via activation of JNK and subsequent phosphorylation of Bcl-2.
“In a study of A53T α-syn degradation, inhibition of ROCK in SH-SY5Y cells increased autophagy via activation of JNK and subsequent phosphorylation of Bcl-2.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [145]
Cited by
Sorted by citations
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationRhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
- Authors
- Liu, F.-T., Yang, Y.-J., Wu, J.-J., Li, S., Tang, Y.-L., Zhao, J., Liu, Z.-Y., Xiao, B.-G., Zuo, J., Liu, W., & Wang, J.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Liu, Wen
- Wang, Jian
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 1632
- Pages
- 9-18
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2191888175
- Cited by
- 39
- References
- 0
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 1
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of China (81371413)
- Science and Technology Commission of Shanghai Municipality (13JC1401100/101, 13JC1401103)
- Shanghai Municipal Commission of Health and Family Planning (XBR2013088)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- fasudil, ROCK inhibitor, alpha-synuclein, A53T alpha-synuclein, Parkinson's disease, autophagy, JNK1, Bcl-2, Beclin-1, Vps34, ROCK2, neurite outgrowth, neurotoxicity, protein clearance
- MeSH terms
- Beclin-1, Autophagy, Humans, Membrane Proteins, Signal Transduction, Proto-Oncogene Proteins c-bcl-2, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Cell Line, Tumor, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 8, Apoptosis Regulatory Proteins, alpha-Synuclein, rho-Associated Kinases
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