Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119302499 |
| _version_ | 1818724451372498944 |
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| author | Helle Bogetofte Pia Jensen Justyna Okarmus Sissel Ida Schmidt Mikkel Agger Matias Ryding Peter Nørregaard Christina Fenger Xianmin Zeng Jesper Graakjær Brent James Ryan Richard Wade-Martins Martin Røssel Larsen Morten Meyer |
| author_facet | Helle Bogetofte Pia Jensen Justyna Okarmus Sissel Ida Schmidt Mikkel Agger Matias Ryding Peter Nørregaard Christina Fenger Xianmin Zeng Jesper Graakjær Brent James Ryan Richard Wade-Martins Martin Røssel Larsen Morten Meyer |
| author_sort | Helle Bogetofte |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T21:26:37Z |
| format | Article |
| id | doaj.art-e98e9afd23534172af5a503933362700 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:26:37Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e98e9afd23534172af5a5039333627002022-12-21T21:32:02ZengElsevierNeurobiology of Disease1095-953X2019-12-01132Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutationHelle Bogetofte0Pia Jensen1Justyna Okarmus2Sissel Ida Schmidt3Mikkel Agger4Matias Ryding5Peter Nørregaard6Christina Fenger7Xianmin Zeng8Jesper Graakjær9Brent James Ryan10Richard Wade-Martins11Martin Røssel Larsen12Morten Meyer13Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, Denmark; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, South Parks Road, University of Oxford, OX1 3QX Oxford, UKDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK5230 Odense M, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, DenmarkBuck Institute for Research on Ageing, 8001 Redwood Boulevard, Novato, CA 94945, USADepartment of Clinical Genetics, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, DenmarkOxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, South Parks Road, University of Oxford, OX1 3QX Oxford, UKOxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, South Parks Road, University of Oxford, OX1 3QX Oxford, UKDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK5230 Odense M, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st, DK5000 Odense C, Denmark; BRIDGE, Brain Research – Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloews Vej 19, DK5000 Odense C, Denmark; Corresponding author at: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winsloewparken 21, st, DK-5000 Odense C, Denmark.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.http://www.sciencedirect.com/science/article/pii/S0969996119302499Parkinson's diseaseiPSCsIsogenicProteomicsPost-translational modificationsNeurite outgrowth |
| spellingShingle | Helle Bogetofte Pia Jensen Justyna Okarmus Sissel Ida Schmidt Mikkel Agger Matias Ryding Peter Nørregaard Christina Fenger Xianmin Zeng Jesper Graakjær Brent James Ryan Richard Wade-Martins Martin Røssel Larsen Morten Meyer Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation Neurobiology of Disease Parkinson's disease iPSCs Isogenic Proteomics Post-translational modifications Neurite outgrowth |
| title | Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation |
| title_full | Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation |
| title_fullStr | Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation |
| title_full_unstemmed | Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation |
| title_short | Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation |
| title_sort | perturbations in rhoa signalling cause altered migration and impaired neuritogenesis in human ipsc derived neural cells with park2 mutation |
| topic | Parkinson's disease iPSCs Isogenic Proteomics Post-translational modifications Neurite outgrowth |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119302499 |
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