Titre :

Protein phosphatase 2A holoenzymes regulate leucine-rich repeat kinase 2 phosphorylation and accumulation

Auteur(s) :

Drouyer, Matthieu [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Bolliger, Marc F. [Auteur]
Lobbestael, Evy [Auteur]
Van den Haute, Chris [Auteur]
Emanuele, Marco [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Lefebvre, Reginald [Auteur]
Sibran, William [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
De Wit, Tina [Auteur]
Leghay, Coline [Auteur]
Mutez, Eugénie [Auteur]
Dzamko, Nicolas [Auteur]
Halliday, Glenda M. [Auteur]
Murayama, Shigeo [Auteur]
Martoriati, Alain [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Cailliau, Katia [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Bodart, Jean-Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Chartier-Harlin, Marie-Christine [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Baekelandt, Veerle [Auteur]
Nichols, R. Jeremy [Auteur]
Taymans, Jean-Marc [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Emanuele, Marco [Auteur]

Titre de la revue :

Neurobiology of Disease

Nom court de la revue :

Neurobiology of Disease

Numéro :

157

Pagination :

105426

Éditeur :

Elsevier BV

Date de publication :

2021-09

ISSN :

0969-9961

Mot(s)-clé(s) en anglais :

LRRK2
Phosphatases
Phosphorylation
Ubiquitination
Parkinson’s disease
PP2A
CRISPR

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

LRRK2 is a highly phosphorylated multidomain protein and mutations in the gene encoding LRRK2 are a major genetic determinant of Parkinson's disease (PD). Dephosphorylation at LRRK2's S910/S935/S955/S973 phosphosite cluster ...
Lire la suite >LRRK2 is a highly phosphorylated multidomain protein and mutations in the gene encoding LRRK2 are a major genetic determinant of Parkinson's disease (PD). Dephosphorylation at LRRK2's S910/S935/S955/S973 phosphosite cluster is observed in several conditions including in sporadic PD brain, in several disease mutant forms of LRRK2 and after pharmacological LRRK2 kinase inhibition. However, the mechanism of LRRK2 dephosphorylation is poorly understood. We performed a phosphatome-wide reverse genetics screen to identify phosphatases involved in the dephosphorylation of the LRRK2 phosphosite S935. Candidate phosphatases selected from the primary screen were tested in mammalian cells, Xenopus oocytes and in vitro. Effects of PP2A on endogenous LRRK2 phosphorylation were examined via expression modulation with CRISPR/dCas9. Our screening revealed LRRK2 phosphorylation regulators linked to the PP1 and PP2A holoenzyme complexes as well as CDC25 phosphatases. We showed that dephosphorylation induced by different kinase inhibitor triggered relocalisation of phosphatases PP1 and PP2A in LRRK2 subcellular compartments in HEK-293 T cells. We also demonstrated that LRRK2 is an authentic substrate of PP2A both in vitro and in Xenopus oocytes. We singled out the PP2A holoenzyme PPP2CA:PPP2R2 as a powerful phosphoregulator of pS935-LRRK2. Furthermore, we demonstrated that this specific PP2A holoenzyme induces LRRK2 relocalization and triggers LRRK2 ubiquitination, suggesting its involvement in LRRK2 clearance. The identification of the PPP2CA:PPP2R2 complex regulating LRRK2 S910/S935/S955/S973 phosphorylation paves the way for studies refining PD therapeutic strategies that impact LRRK2 phosphorylation.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Équipe(s) de recherche :

Régulation des signaux de division
Chemical Glycobiology

Date de dépôt :

2021-10-08T14:36:54Z
2021-10-11T10:38:02Z