Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation
Open accessAbstract
Mutations in parkin, encoded by the PARK2 gene, causes early-onset familial Parkinson's disease (PD), but dysfunctional parkin has also been implicated in sporadic PD. By combining human isogenic induced pluripotent stem cells (iPSCs) with and without PARK2 knockout (KO) and a novel large-scale mass spectrometry based proteomics and post-translational modification (PTM)-omics approach, we have mapped changes in protein profiles and PTMs caused by parkin deficiency in neurons. Our study identifies changes to several proteins previously shown to be dysregulated in brains of sporadic PD patients. Pathway analysis and subsequent in vitro assays reveal perturbations in migration and neurite outgrowth in the PARK2 KO neurons. We confirm the neurite defects using long-term engraftment of neurons in the striatum of immunosuppressed hemiparkinsonian adult rats. The GTP-binding protein RhoA was identified as a key upstream regulator, and RhoA activity was significantly increased in PARK2 KO neurons. By inhibiting RhoA signalling the migration and neurite outgrowth phenotypes could be rescued. Our study provides new insight into the pathogenesis of PD and demonstrates the broadly applicable potential of proteomics and PTMomics for elucidating the role of disease-causing mutations.
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RhoA signaling is increased in human-induced pluripotent stem cell-derived neurons with mutation in the PD-associated gene PARK2.
“In line with these observations, we recently showed that RhoA signaling is increased in human-induced pluripotent stem cell-derived neurons with mutation in the PD-associated gene PARK2.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [178]
Increased RhoA activity in PARK2 mutant neurons alters migration and impairs neuritogenesis, which can be rescued by Rhosin-mediated RhoA inhibition.
“Increased RhoA activity was found to alter migration and impair neuritogenesis, which could be rescued by Rhosin-mediated RhoA inhibition [178].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [178]
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1 retracted
RETRACTED ARTICLE: Parkin and PINK1 mitigate STING-induced inflammation
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RetractedJiang, H., Ren, Y., Yuen, E. Y., Zhong, P., Ghaedi, M., Hu, Z., Azabdaftari, G., Nakaso, K., Yan, Z., & Feng, J. (2012) · Nature Communications · doi:10.1038/ncomms1669 · Cited by 254 · see citing works
Astrocyte reactivity after brain injury—: The role of galectins 1 and 3
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You, Y., Borgmann, K., Edara, V. V., Stacy, S., Ghorpade, A., & Ikezu, T. (2020) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2019.1706801 · Cited by 176 · see citing works
RhoA 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
Self-citationScientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation
Koch, K., Bartmann, K., Hartmann, J., Kapr, J., Klose, J., Kuchovská, E., Pahl, M., Schlüppmann, K., Zühr, E., & Fritsche, E. (2022) · Frontiers in Toxicology · doi:10.3389/ftox.2022.816370 · Cited by 48 · see citing works
- Authors
- Bogetofte, H., Jensen, P., Okarmus, J., Schmidt, S. I., Agger, M., Ryding, M., Nørregaard, P., Fenger, C., Zeng, X., Graakjær, J., Ryan, B. J., Wade-Martins, R., Larsen, M. R., & Meyer, M.
- Affiliations
- University of Southern Denmark (DK)
- Buck Institute for Research on Aging (US)
- Vejle Sygehus (DK)
- University of Oxford (GB)
- Corresponding author
- Meyer, Morten
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 132
- Pages
- 104581
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2969828274
- Cited by
- 35
- References
- 3
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 1
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by-nc-nd)
- Funders
- Innovationsfonden
- Lundbeckfonden
- Jascha Fonden
- Syddansk Universitet
- Fonden til Lægevidenskabens Fremme
- Parkinsonforeningen
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- Parkin, PARK2 mutations, Parkinson's disease, RhoA signaling, neuronal migration, neurite outgrowth, iPSC-derived neurons, post-translational modification, proteomics, hemiparkinsonian rat model, sporadic Parkinson's disease
- MeSH terms
- Animals, Cell Movement, Humans, Mutation, Parkinson Disease, Signal Transduction, rhoA GTP-Binding Protein, Ubiquitin-Protein Ligases, Rats, Neurogenesis, Gene Knockout Techniques, Induced Pluripotent Stem Cells, Dopaminergic Neurons
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