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A Phosphosite Mutant Approach on LRRK2 Links Phosphorylation and Dephosphorylation to Protective and Deleterious Markers, Respectively

Authors :
Antoine Marchand
Alessia Sarchione
Panagiotis S. Athanasopoulos
Hélène Bauderlique-Le Roy
Liesel Goveas
Romain Magnez
Matthieu Drouyer
Marco Emanuele
Franz Y. Ho
Maxime Liberelle
Patricia Melnyk
Nicolas Lebègue
Xavier Thuru
R. Jeremy Nichols
Elisa Greggio
Arjan Kortholt
Thierry Galli
Marie-Christine Chartier-Harlin
Jean-Marc Taymans
Source :
Cells, Vol 11, Iss 6, p 1018 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a major genetic determinant of Parkinson’s disease (PD), encoding a homonymous multi-domain protein with two catalytic activities, GTPase and Kinase, involved in intracellular signaling and trafficking. LRRK2 is phosphorylated at multiple sites, including a cluster of autophosphorylation sites in the GTPase domain and a cluster of heterologous phosphorylation sites at residues 860 to 976. Phosphorylation at these latter sites is found to be modified in brains of PD patients, as well as for some disease mutant forms of LRRK2. The main aim of this study is to investigate the functional consequences of LRRK2 phosphorylation or dephosphorylation at LRRK2’s heterologous phosphorylation sites. To this end, we generated LRRK2 phosphorylation site mutants and studied how these affected LRRK2 catalytic activity, neurite outgrowth and lysosomal physiology in cellular models. We show that phosphorylation of RAB8a and RAB10 substrates are reduced with phosphomimicking forms of LRRK2, while RAB29 induced activation of LRRK2 kinase activity is enhanced for phosphodead forms of LRRK2. Considering the hypothesis that PD pathology is associated to increased LRRK2 kinase activity, our results suggest that for its heterologous phosphorylation sites LRRK2 phosphorylation correlates to healthy phenotypes and LRRK2 dephosphorylation correlates to phenotypes associated to the PD pathological processes.

Details

Language :
English
ISSN :
20734409
Volume :
11
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.18bf45a023c0403281af9f78d80acdf0
Document Type :
article
Full Text :
https://doi.org/10.3390/cells11061018