1. Cell Biology
  2. Neuroscience
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TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

  1. Emily Bowie
  2. Sarah C Goetz  Is a corresponding author
  1. Duke University, United States
Research Article
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Cite this article as: eLife 2020;9:e51166 doi: 10.7554/eLife.51166

Abstract

Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. These structures are essential for the development of many tissues and organs, however, their function in adult tissues, particularly neurons in the brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated in a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11). Here, we show that conditional knockout of Ttbk2 in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of SCA11 including motor coordination deficits and defects to Purkinje cell (PC) integrity. We also find that the Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 knockout, indicating that disruption of ciliary signaling is a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining the function of PCs in the adult cerebellum and reveal novel insights into mechanisms involved in neurodegeneration.

Article and author information

Author details

  1. Emily Bowie

    University Program in Genetics and Genomics, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5694-6044
  2. Sarah C Goetz

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    For correspondence
    sarah.c.goetz@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9705-6390

Funding

National Institutes of Health (R00 HD076444)

  • Sarah C Goetz

National Ataxia Foundation (Young Investigator award)

  • Sarah C Goetz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (Protocol #A218-17-09) of Duke University. Every effort was made to minimize animal suffering

Reviewing Editor

  1. Jeremy F Reiter, University of California, San Francisco, United States

Publication history

  1. Received: August 17, 2019
  2. Accepted: January 13, 2020
  3. Accepted Manuscript published: January 14, 2020 (version 1)

Copyright

© 2020, Bowie & Goetz

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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