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Accession Number:
ADA566921
Title:
LRRK2 Mediated Changes in TAU Phosphorylation
Descriptive Note:
Final rept. 4 Apr 2011-3 Sep2 012
Corporate Author:
PARKINSONS INST SUNNYVALE CA
Report Date:
2012-10-01
Pagination or Media Count:
9.0
Abstract:
The gene encoding the protein kinase LRRK2 is the most frequently mutated gene in familial Parkinsons disease PD. The microtubule associated protein Tau is a pathological component of Alzheimers disease and genome wide associations studies implicate Tau in PD. In several mouse models it has been shown that Tau exhibits a LRRK2 dependent change in phosphorylation status. The confluence of evidence that these two disease proteins may intersect in disease pathogenesis yielded the hypothesis that LRRK2 kinase activity potentiated the phosphorylation of Tau. We originally proposed to investigate known tau kinases as being stimulated by LRRK2 activity to modify tau, but we subsequently identified that LRRK2 can directly phosphorylate Tau. We found that LRRK2 can phosphorylate Tau and that this modification is enhanced in shorter splice forms of Tau non-441 splice variants and that addition of tubulin to kinase reactions enhanced the phosphorylation. We mapped 6 LRRK2 phosphosites on Tau using mass spectrometry T149, T169, T205, S210, T217AND T263. We prepared 15 different Tau phosphomutants and purified them as recombinant proteins from bacteria. We tested the effects of these mutations on tubulin assembly and LRRK2 mediated phosphorylation. We found that only three mutants increased tubulin assembly Thr169, Thr181 and S210. Unfortunately, we failed to completely ablate LRRK2 phosphorylation of any of the mutants we generated, indicating still more sites of LRRK2 phosphorylation, meaning more studies are required to understand the role of LRRK2 in phosphorylating and regulating Tau function.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
