Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.
| dc.contributor.author | Bowie, Emily | |
| dc.contributor.author | Norris, Ryan | |
| dc.contributor.author | Anderson, Kathryn V | |
| dc.contributor.author | Goetz, Sarah C | |
| dc.contributor.editor | Dutcher, Susan K | |
| dc.date.accessioned | 2019-02-22T14:58:10Z | |
| dc.date.available | 2019-02-22T14:58:10Z | |
| dc.date.issued | 2018-12-10 | |
| dc.date.updated | 2019-02-22T14:58:07Z | |
| dc.description.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. | |
| dc.identifier | PGENETICS-D-18-00974 | |
| dc.identifier.issn | 1553-7390 | |
| dc.identifier.issn | 1553-7404 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | Public Library of Science (PLoS) | |
| dc.relation.ispartof | PLoS genetics | |
| dc.relation.isversionof | 10.1371/journal.pgen.1007844 | |
| dc.title | Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability. | |
| dc.type | Journal article | |
| pubs.begin-page | e1007844 | |
| pubs.issue | 12 | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Cell Biology | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Pharmacology & Cancer Biology | |
| pubs.organisational-group | Student | |
| pubs.publication-status | Published | |
| pubs.volume | 14 |
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