LRRK2 Facilitates tau Phosphorylation through Strong Interaction with tau and cdk5.
Biochemistry
; 54(33): 5198-208, 2015 Aug 25.
Article
en En
| MEDLINE
| ID: mdl-26268594
ABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) and tau have been identified as risk factors of Parkinson's disease (PD). As LRRK2 is a kinase and tau is hyperphosphorylated in some LRRK2 mutation carriers of PD patients, the obvious hypothesis is that tau could be a substrate of LRRK2. Previous reports that LRRK2 phosphorylates free tau or tubulin-associated tau provide direct support for this proposition. By comparing LRRK2 with cdk5, we show that wild-type LRRK2 and the G2019S mutant phosphorylate free recombinant full-length tau protein with specific activity 480- and 250-fold lower than cdk5, respectively. More strikingly tau binds to wt LRRK2 or the G2019S mutant 140- or 200-fold more strongly than cdk5. The extremely low activity of LRRK2 but strong binding affinity with tau suggests that LRRK2 may facilitate tau phosphorylation as a scaffold protein rather than as a major tau kinase. This hypothesis is further supported by the observation that (i) cdk5 or tau coimmunoprecipitates with endogenous LRRK2 in SH-SY5Y cells, in mouse brain tissue, and in human PBMCs; (ii) knocking down endogenous LRRK2 by its siRNA in SH-SY5Y cells reduces tau phosphorylation at Ser396 and Ser404; (iii) inhibiting LRRK2 kinase activity by its inhibitors has no effect on tau phosphorylation at these two sites; and (iv) overexpressing wt LRRK2, the G2019S mutant, or the D1994A kinase-dead mutant in SH-SY5Y cells has no effect on tau phosphorylation. Our results suggest that LRRK2 facilitates tau phosphorylation indirectly by recruiting tau or cdk5 rather than by directly phosphorylating tau.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas tau
/
Proteínas Serina-Treonina Quinasas
/
Quinasa 5 Dependiente de la Ciclina
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Biochemistry
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos