title: β-Tubulin mutations that cause severe neuropathies disrupt axonal transport.
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.
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Niwa
authors.forename: Hironori
authors.initials: H
authors.lastname: Takahashi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hirokawa
mesh_terms: D001370:Axonal Transport / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D016472:Motor Neuron Disease / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D014404:Tubulin; D050988:Vesicle-Associated Membrane Protein 2; D016547:Kinesins