Re-circulating Phagocytes Loaded with CNS Debris: A Potential Marker of Neurodegeneration in Parkinsons Disease?

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.

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Biofluid-based Biomarkers for Parkinsons Disease: A New Paradigm

Khoo

2015

AIMS Medical Science

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Re-circulating Phagocytes Loaded with CNS Debris: A Potential Marker of Neurodegeneration in Parkinsons Disease?

Cited by 5 publications

References 12 publications

Therapeutic efficacy of olfactory stem cells in rotenone induced Parkinsonism in adult male albino rats

Therapeutic efficacy of olfactory stem cells in rotenone induced Parkinsonism in adult male albino rats

LRRK2 Facilitates tau Phosphorylation through Strong Interaction with tau and cdk5

Biofluid-based Biomarkers for Parkinsons Disease: A New Paradigm

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