Investigation of the physiological function of TTBK2 (tau tubulin kinase 2), a protein kinase mutated in spinocerebellar ataxia type 11 (SCA11)
type: CreativeWork
description: TTBK2 was first identified based on its physical association with microtubules and its ability to phosphorylate microtubule-associated proteins (tau, tubulin, MAP2) in vitro (Takahashi et al., 1995, Tomizawa et al., 2001). Since this discovery by Japanese scientists in 1995, considerable work has been invested in examining TTBK2’s relationship with aberrant tau phosphorylation and neurodegeneration in Alzheimer’s disease. However, these studies have never been substantiated in vivo. The identification of TTBK2 truncating mutations as the cause of spinocerebellar ataxia type 11 (SCA11), in 2007, emphasised that TTBK2 has a prominent physiological role in the nervous system. When I started my PhD, there was little known about TTBK2 and many fundamental questions about TTBK2 remained unanswered. In Chapter 3, I describe an initial analysis of TTBK2 substrate specificity by using an unbiased positional scanning peptide library and show that it has a conspicuous preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. This information was then exploited to develop an optimised peptide substrate, named TTBKtide, to assess TTBK2 catalytic activity. TTBKtide was used to demonstrate that SCA11 truncating mutations lead to marked inhibition of TTBK2 kinase activity. The identification of TTBK2’s interacting proteins was of paramount importance to advance our understanding of both biological and disease processes. Identifying and characterising the key targets (substrates) of TTBK2 in the nervous system would provide vital new insights into the physiological role of TTBK2, which in turn, may uncover the molecular pathogenic mechanism underpinning the development of spinocerebellar ataxia type 11 (SCA11). To this end, I identified a number of TTBK2 interactors by co-immunoprecipitation of endogenous TTBK2 from mouse brain homogenates (Chapter 4). This screen provided tantalising evidence that TTBK2 operates in a distinct step of the syna…
abstract: TTBK2 was first identified based on its physical association with microtubules and its ability to phosphorylate microtubule-associated proteins (tau, tubulin, MAP2) in vitro (Takahashi et al., 1995, Tomizawa et al., 2001). Since this discovery by Japanese scientists in 1995, considerable work has been invested in examining TTBK2’s relationship with aberrant tau phosphorylation and neurodegeneration in Alzheimer’s disease. However, these studies have never been substantiated in vivo. The identification of TTBK2 truncating mutations as the cause of spinocerebellar ataxia type 11 (SCA11), in 2007, emphasised that TTBK2 has a prominent physiological role in the nervous system. When I started my PhD, there was little known about TTBK2 and many fundamental questions about TTBK2 remained unanswered. In Chapter 3, I describe an initial analysis of TTBK2 substrate specificity by using an unbiased positional scanning peptide library and show that it has a conspicuous preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. This information was then exploited to develop an optimised peptide substrate, named TTBKtide, to assess TTBK2 catalytic activity. TTBKtide was used to demonstrate that SCA11 truncating mutations lead to marked inhibition of TTBK2 kinase activity. The identification of TTBK2’s interacting proteins was of paramount importance to advance our understanding of both biological and disease processes. Identifying and characterising the key targets (substrates) of TTBK2 in the nervous system would provide vital new insights into the physiological role of TTBK2, which in turn, may uncover the molecular pathogenic mechanism underpinning the development of spinocerebellar ataxia type 11 (SCA11). To this end, I identified a number of TTBK2 interactors by co-immunoprecipitation of endogenous TTBK2 from mouse brain homogenates (Chapter 4). This screen provided tantalising evidence that TTBK2 operates in a distinct step of the syna…
author: Esoof, Noor
language: eng
date published: 2014
date modified: 2026-07-24T02:08:05Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee