Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function

• Koji Ikegami

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Robb L. Heier

  Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940;

• Midori Taruishi

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Hiroshi Takagi

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Masahiro Mukai

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Shuichi Shimma

  National Institute for Physiological Sciences, Okazaki, Aichi 444-8787, Japan;

• Shu Taira

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Ken Hatanaka

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Nobuhiro Morone

  Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; and

• Ikuko Yao

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

• Patrick K. Campbell

  Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940;

• Shigeki Yuasa

  Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; and

• Carsten Janke

  **Centre de Rechérches en Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, 34293 Montpellier, France

• Grant R. MacGregor

  Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940;

• Mitsutoshi Setou

  *Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan;

抄録

Microtubules function as molecular tracks along which motor proteins transport a variety of cargo to discrete destinations within the cell. The carboxyl termini of α- and β-tubulin can undergo different posttranslational modifications, including polyglutamylation, which is particularly abundant within the mammalian nervous system. Thus, this modification could serve as a molecular “traffic sign” for motor proteins in neuronal cells. To investigate whether polyglutamylated α-tubulin could perform this function, we analyzed ROSA22 mice that lack functional PGs1, a subunit of α-tubulin-selective polyglutamylase. In wild-type mice, polyglutamylated α-tubulin is abundant in both axonal and dendritic neurites. ROSA22 mutants display a striking loss of polyglutamylated α-tubulin within neurons, including their neurites, which is associated with decreased binding affinity of certain structural microtubule-associated proteins and motor proteins, including kinesins, to microtubules purified from ROSA22-mutant brain. Of the kinesins examined, KIF1A, a subfamily of kinesin-3, was less abundant in neurites from ROSA22 mutants in vitro and in vivo , whereas the distribution of KIF3A (kinesin-2) and KIF5 (kinesin-1) appeared unaltered. The density of synaptic vesicles, a cargo of KIF1A, was decreased in synaptic terminals in the CA1 region of hippocampus in ROSA22 mutants. Consistent with this finding, ROSA22 mutants displayed more rapid depletion of synaptic vesicles than wild-type littermates after high-frequency stimulation. These data provide evidence for a role of polyglutamylation of α-tubulin in vivo , as a molecular traffic sign for targeting of KIF1 kinesin required for continuous synaptic transmission.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 104 (9), 3213-3218, 2007-02-27

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1363670318249396608
• NII論文ID: 80017885013
• DOI: 10.1073/pnas.0611547104
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0611547104
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