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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Abstrakt

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

Bibliografisk note

Copyright © 2018. Published by Elsevier Inc.

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