Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability Journal Article
| Authors: | Bowie, E.; Norris, R.; Anderson, K. V.; Goetz, S. C. |
| Article Title: | Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability |
| Abstract: | 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. © 2018 Bowie et al. http://creativecommons.org/licenses/by/4.0/. |
| Journal Title: | PLoS Genetics |
| Volume: | 14 |
| Issue: | 12 |
| ISSN: | 1553-7390 |
| Publisher: | Public Library of Science |
| Date Published: | 2018-12-10 |
| Start Page: | e1007844 |
| Language: | English |
| DOI: | 10.1371/journal.pgen.1007844 |
| PUBMED: | 30532139 |
| PROVIDER: | scopus |
| PMCID: | PMC6307817 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2019 -- Source: Scopus |
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