Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation

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*

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer104581
TidsskriftNeurobiology of Disease
Vol/bind132
Antal sider14
ISSN0969-9961
DOI
StatusUdgivet - dec. 2019

Fingeraftryk

Parkinson Disease
Neurons
Mutation
rhoA GTP-Binding Protein
Proteins

Bibliografisk note

Copyright © 2018. Published by Elsevier Inc.

Citer dette

Bogetofte, Helle ; Jensen, Pia ; Okarmus, Justyna ; Schmidt, Sissel Ida ; Agger, Mikkel ; Ryding, Matias ; Nørregaard, Peter ; Fenger, Christina ; Zeng, Xianmin ; Graakjær, Jesper ; Ryan, Brent James ; Wade-Martins, Richard ; Larsen, Martin Røssel ; Meyer, Morten. / Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation. I: Neurobiology of Disease. 2019 ; Bind 132.
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title = "Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation",
abstract = "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.",
author = "Helle Bogetofte and Pia Jensen and Justyna Okarmus and Schmidt, {Sissel Ida} and Mikkel Agger and Matias Ryding and Peter N{\o}rregaard and Christina Fenger and Xianmin Zeng and Jesper Graakj{\ae}r and Ryan, {Brent James} and Richard Wade-Martins and Larsen, {Martin R{\o}ssel} and Morten Meyer",
note = "Copyright {\circledC} 2018. Published by Elsevier Inc.",
year = "2019",
month = "12",
doi = "10.1016/j.nbd.2019.104581",
language = "English",
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Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation. / Bogetofte, Helle; Jensen, Pia; Okarmus, Justyna; Schmidt, Sissel Ida; Agger, Mikkel; Ryding, Matias; Nørregaard, Peter; Fenger, Christina; Zeng, Xianmin; Graakjær, Jesper; Ryan, Brent James; Wade-Martins, Richard; Larsen, Martin Røssel; Meyer, Morten.

I: Neurobiology of Disease, Bind 132, 104581, 12.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation

AU - Bogetofte, Helle

AU - Jensen, Pia

AU - Okarmus, Justyna

AU - Schmidt, Sissel Ida

AU - Agger, Mikkel

AU - Ryding, Matias

AU - Nørregaard, Peter

AU - Fenger, Christina

AU - Zeng, Xianmin

AU - Graakjær, Jesper

AU - Ryan, Brent James

AU - Wade-Martins, Richard

AU - Larsen, Martin Røssel

AU - Meyer, Morten

N1 - Copyright © 2018. Published by Elsevier Inc.

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.nbd.2019.104581

DO - 10.1016/j.nbd.2019.104581

M3 - Journal article

C2 - 31445161

VL - 132

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

M1 - 104581

ER -