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Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.

Publication ,  Journal Article
Bowie, E; Norris, R; Anderson, KV; Goetz, SC
Published in: PLoS Genet
December 2018

Spinocerebellar ataxia type 11 (SCA11) is a rare, dominantly inherited human ataxia characterized by atrophy of Purkinje neurons in the cerebellum. SCA11 is caused by mutations in the gene encoding the Serine/Threonine kinase Tau tubulin kinase 2 (TTBK2) that result in premature truncations of the protein. We previously showed that TTBK2 is a key regulator of the assembly of primary cilia in vivo. However, the mechanisms by which the SCA11-associated mutations disrupt TTBK2 function, and whether they interfere with ciliogenesis were unknown. In this work, we present evidence that SCA11-associated mutations are dominant negative alleles and that the resulting truncated protein (TTBK2SCA11) interferes with the function of full length TTBK2 in mediating ciliogenesis. A Ttbk2 allelic series revealed that upon partial reduction of full length TTBK2 function, TTBK2SCA11 can interfere with the activity of the residual wild-type protein to decrease cilia number and interrupt cilia-dependent Sonic hedgehog (SHH) signaling. Our studies have also revealed new functions for TTBK2 after cilia initiation in the control of cilia length, trafficking of a subset of SHH pathway components, including Smoothened (SMO), and cilia stability. These studies provide a molecular foundation to understand the cellular and molecular pathogenesis of human SCA11, and help account for the link between ciliary dysfunction and neurodegenerative diseases.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

December 2018

Volume

14

Issue

12

Start / End Page

e1007844

Location

United States

Related Subject Headings

  • Spinocerebellar Ataxias
  • Protein Serine-Threonine Kinases
  • Mutation
  • Microscopy, Electron, Transmission
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
  • Homozygote
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bowie, E., Norris, R., Anderson, K. V., & Goetz, S. C. (2018). Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability. PLoS Genet, 14(12), e1007844. https://doi.org/10.1371/journal.pgen.1007844
Bowie, Emily, Ryan Norris, Kathryn V. Anderson, and Sarah C. Goetz. “Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.PLoS Genet 14, no. 12 (December 2018): e1007844. https://doi.org/10.1371/journal.pgen.1007844.
Bowie E, Norris R, Anderson KV, Goetz SC. Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability. PLoS Genet. 2018 Dec;14(12):e1007844.
Bowie, Emily, et al. “Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.PLoS Genet, vol. 14, no. 12, Dec. 2018, p. e1007844. Pubmed, doi:10.1371/journal.pgen.1007844.
Bowie E, Norris R, Anderson KV, Goetz SC. Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability. PLoS Genet. 2018 Dec;14(12):e1007844.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

December 2018

Volume

14

Issue

12

Start / End Page

e1007844

Location

United States

Related Subject Headings

  • Spinocerebellar Ataxias
  • Protein Serine-Threonine Kinases
  • Mutation
  • Microscopy, Electron, Transmission
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
  • Homozygote