Title

TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.

Journal

The Biochemical journal

Volume

437

Issue

None

Pages

157-67

Date

2011-07-01

Authors

Alessi DR | Begley MJ | Bouskila M | Cantley LC | Deak M | Esoof N | Fang EH | Gay L | Prescott A | Storey KG

Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037).

TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.

SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. Using a SCA11-mutation-carrying knockin mouse we show that this leads to inhibition of endogenous TTBK2 protein kinase activity.

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