Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nature - Genetics

Department of Molecular Neuroscience, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Nature Genetics (Impact Factor: 29.35). 02/2008; 39(12):1434-6. DOI: 10.1038/ng.2007.43
Source: PubMed


The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.

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Available from: Tammaryn Lashley, Aug 26, 2014
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    • "This result supports our hypothesis that TTBK2 regulates cell migration through KIF2A inhibition and control of MT dynamics. We examined the involvement of TTBK2 in the migration of cerebellar granule neurons because TTBK2 may be involved in normal cerebellar development and tissue homeostasis (Houlden et al., 2007). The cerebellums of mice on postnatal day 5 were electroporated with an shRNA expression vector and mCherry and fixed at postnatal day 7 to monitor the migration of granule neurons from the external granular layer toward the internal granular layer (IGL) through the molecular layer (ML; Fig. 7 "
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    ABSTRACT: Microtubules (MTs) play critical roles in various cellular events, including cell migration. End-binding proteins (EBs) accumulate at the ends of growing MTs and regulate MT end dynamics by recruiting other plus end-tracking proteins (+TIPs). However, how EBs contribute to MT dynamics through +TIPs remains elusive. We focused on tau-tubulin kinase 2 (TTBK2) as an EB1/3-binding kinase and confirmed that TTBK2 acted as a +TIP. We identified MT-depolymerizing kinesin KIF2A as a novel substrate of TTBK2. TTBK2 phosphorylated KIF2A at S135 in intact cells in an EB1/3-dependent fashion and inactivated its MT-depolymerizing activity in vitro. TTBK2 depletion reduced MT lifetime (facilitated shrinkage and suppressed rescue) and impaired HeLa cell migration, and these phenotypes were partially restored by KIF2A co-depletion. Expression of nonphosphorylatable KIF2A, but not wild-type KIF2A, reduced MT lifetime and slowed down the cell migration. These findings indicate that TTBK2 with EB1/3 phosphorylates KIF2A and antagonizes KIF2A-induced depolymerization at MT plus ends for cell migration. © 2015 Watanabe et al.
    The Journal of Cell Biology 08/2015; 210(5):737-751. DOI:10.1083/jcb.201412075 · 9.83 Impact Factor
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    • "Mice lacking tau tubulin kinase 2 (TTBK2), a microtubule-associated kinase, fail ciliogenesis and exhibit neural tube defects (Goetz et al., 2012). This same gene with truncating mutations around residues 122–137 causes dominant spinocerebellar ataxia type 11 (SCA11) (Houlden et al., 2007). Furthermore, when these truncated cDNAs are transfected into cells there is inhibition of ciliogenesis , suggesting SCA may relate to ciliary defects. "
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    ABSTRACT: Primary cilia were the largely neglected nonmotile counterparts of their better-known cousin, the motile cilia. For years these nonmotile cilia were considered evolutionary remnants of little consequence to cellular function. Fast forward 10 years and we now recognize primary cilia as key integrators of extracellular ligand-based signaling and cellular polarity, which regulate neuronal cell fate, migration, differentiation, as well as a host of adult behaviors. Important future questions will focus on structure-function relationships, their roles in signaling and disease and as areas of target for treatments.
    Neuron 05/2014; 82(3):511-521. DOI:10.1016/j.neuron.2014.04.024 · 15.05 Impact Factor
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    • "Therefore, the degree of TTBK2 gene expression did not associate with pathology in the cerebellum although the gene was highly expressed. TTBK2 truncation mutations found in the SCA11 families resulted in a shorter half-life of mRNA as compared to wildtype TTBK2 mRNA, suggesting the reduction in expression of TTBK2 by the mutations (Houlden et al., 2007). Kraemer et al. (2006) reported the role of TTBK2 in the tau pathway using RNA interference experiments in C. elegans. "
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    ABSTRACT: Tau-tubulin kinase (TTBK) belongs to casein kinase superfamily and phosphorylates microtubule-associated protein tau and tubulin. TTBK has two isoforms, TTBK1 and TTBK2, which contain highly homologous catalytic domains but their non-catalytic domains are distinctly different. TTBK1 is expressed specifically in the central nervous system and is involved in phosphorylation and aggregation of tau. TTBK2 is ubiquitously expressed in multiple tissues and genetically linked to spinocerebellar ataxia type 11. TTBK1 directly phosphorylates tau protein, especially at Ser422, and also activates cycline-dependent kinase 5 in a unique mechanism. TTBK1 protein expression is significantly elevated in Alzheimer's disease (AD) brains, and genetic variations of the TTBK1 gene are associated with late-onset Alzheimer's disease in two cohorts of Chinese and Spanish populations. TTBK1 transgenic mice harboring the entire 55-kilobase genomic sequence of human TTBK1 show progression of tau accumulation, neuroinflammation, and neurodegeneration when crossed with tau mutant mice. Our recent study shows that there is a striking switch in mononuclear phagocyte and activation phenotypes in the anterior horn of the spinal cord from alternatively activated (M2-skewed) microglia in P301L tau mutant mice to pro-inflammatory (M1-skewed) infiltrating peripheral monocytes by crossing the tau mice with TTBK1 transgenic mice. TTBK1 is responsible for mediating M1-activated microglia-induced neurotoxicity, and its overexpression induces axonal degeneration in vitro. These studies suggest that TTBK1 is an important molecule for the inflammatory axonal degeneration, which may be relevant to the pathobiology of tauopathy including AD.
    Frontiers in Molecular Neuroscience 04/2014; 7(1):33. DOI:10.3389/fnmol.2014.00033 · 4.08 Impact Factor
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