β-Tubulin mutations that cause severe neuropathies disrupt axonal transport

Shinsuke Niwa, Hironori Takahashi, Nobutaka Hirokawa

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

Microtubules are fundamental to neuronal morphogenesis and function. Mutations in tubulin, the major constituent of microtubules, result in neuronal diseases. Here, we have analysed β-tubulin mutations that cause neuronal diseases and we have identified mutations that strongly inhibit axonal transport of vesicles and mitochondria. These mutations are in the H12 helix of β-tubulin and change the negative charge on the surface of the microtubule. This surface is the interface between microtubules and kinesin superfamily motor proteins (KIF). The binding of axonal transport KIFs to microtubules is dominant negatively disrupted by these mutations, which alters the localization of KIFs in neurons and inhibits axon elongation in vivo. In humans, these mutations induce broad neurological symptoms, such as loss of axons in the central nervous system and peripheral neuropathy. Thus, our data identified the critical region of β-tubulin required for axonal transport and suggest a molecular mechanism for human neuronal diseases caused by tubulin mutations.

Original languageEnglish
Pages (from-to)1352-1364
Number of pages13
JournalEMBO Journal
Volume32
Issue number10
DOIs
Publication statusPublished - 2013 May 15
Externally publishedYes

Keywords

  • Axonal transport
  • CFEOM3
  • Kinesin
  • TUBB2
  • TUBB3

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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