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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    • ", researchers have been looking for common mechanisms on a molecular level. Gene–gene interaction networks have previously shown that even when SCAs are divided into groups based on mutation type, they still show great overlap in gene co-expression mechanisms (Matilla-Dueñas et al., 2013;Orr et al., 1993) SCA2 ATXN2 Ataxin-2 RNA metabolism (CAG) n (Imbert et al., 1996;Pulst et al., 1996;Sanpei et al., 1996) SCA3 ATXN3 Ataxin-3 Deubiquitination, transcription regulation (CAG) n (Kawaguchi et al., 1994)SCA4 Unknown Unknown Unknown Unknown (Flanigan et al., 1996)Zhuchenko et al., 1997) SCA7 ATXN7 Ataxin-7 Transcription regulation (CAG) n (David et al., 1997) SCA8 KLHL1AS/ATXN8 Kelch-like 1/Ataxin-8 Unknown Intronic (CTG) n (Koob et al., 1999) SCA9 Reserved Unknown Unknown Unknown (Higgins et al., 1997) SCA10 ATXN10 Ataxin-10 Neuritogenesis (ATTCT) n (Matsuura et al., 2000) SCA11 TTBK2 Tau Tubulin Kinase 2 Implicated in tau phosphorylation Deletion (Houlden et al., 2007) SCA12 PPP2R2B Protein phosphatase 2 (formerly 2A), regulatory subunit B Regulation of PP2 activity, transcription regulation 5′-UTR (CAG) n (Holmes et al., 1999)Huang et al., 2012)SCA30 Unknown Unknown Unknown Unknown (Storey et al., 2009) SCA31 TK2 or BEAN Unknown Unknown Intronic (TGGAA) n (Sato et al., 2009) SCA32 Reserved SCA33 Reserved SCA34 ELOVL4 Elongation of very long chain fatty acids protein 4 Elongation of fatty acids MM (Cadieux-Dion et al., 2014) SCA35 TGM6 Transglutaminase 6 Crosslinking of proteins, conjugation of polyamines to proteins MM (Wang et al., 2010) SCA36 NOP56 NOP56 ribonucleoprotein homolog 60S ribosomal subunit biogenesis (early & middle stages) Intronic (GGCCTC) n (Kobayashi et al., 2011) SCA37 Unknown Unknown Unknown Unknown (Serrano-Munuera et al., 2013) SCA38 ELOVL5 Elongation of very long chain fatty acids protein 5 Elongation of fatty acids MM (Di Gregorio et al., 2014) SCA39 Unknown Unknown Unknown Chromosomal duplication (Johnson et al., 2015) SCA40 CCDC88C Coiled-coil domain containing 88C Regulation of protein phosphorylation, regulation of Wnt signaling MM (Tsoi et al., 2014) SCA41 TRPC3 Transient receptor potential cation channel, subfamily C, member 3 Receptor-activated non-selective calcium permeant cation channel MM (Fogel et al., 2015)DRPLA ATN1 Atrophin I Transcriptional corepressor (CAG) n (Koide et al., 1994) Undefined RNF170 Ring finger protein 170 E3 ubiquitin ligase activity MM (Valdmanis et al., 2011) Undefined GRID2 Glutamate receptor, Ionotropic, Delta 2 Ionotropic glutamate receptor activity MM (Coutelier et al., 2015)andVerbeek, 2014). Gene–gene interaction networks emerging in all cerebellar ataxias include neurogenesis, cell cycle and proliferation, cell communication, and synaptic transmission, all of which include calcium signaling. "
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    ABSTRACT: The spinocerebellar ataxias (SCAs) form an ever-growing group of neurodegenerative disorders causing dysfunction of the cerebellum and loss of motor control in patients. Currently, 41 different genetic causes have been identified, with each mutation affecting a different gene. Interestingly, these diverse genetic causes all disrupt cerebellar function and produce similar symptoms in patients. In order to understand the disease better, and define possible therapeutic targets for multiple SCAs, the field has been searching for common ground among the SCAs. In this review, we discuss the physiology of climbing fibers and the possibility that climbing fiber dysfunction is a point of convergence for at least a subset of SCAs.
    Full-text · Article · Jan 2016 · Neurobiology of Disease
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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.
    Full-text · Article · Aug 2015 · The Journal of Cell Biology
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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.
    Full-text · Article · May 2014 · Neuron
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