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The Journal of Neuroscience, March 15, 1998, 18(6):2063-2074

Deficiency in Protein L-Isoaspartyl Methyltransferase Results in a Fatal Progressive Epilepsy

Akihiro Yamamoto^{1, 2}, Hideyuki Takagi¹, Daisuke Kitamura³, Hozumi Tatsuoka⁴, Hirotake Nakano⁵, Hitoshi Kawano⁶, Hidehito Kuroyanagi¹, Yu-ichi Yahagi¹, Shin-ichiro Kobayashi¹, Ken-ichi Koizumi¹, Tsuyoshi Sakai¹, Ken-ichi Saito⁷, Tanemichi Chiba⁴, Koki Kawamura⁶, Katsushi Suzuki⁷, Takeshi Watanabe⁸, Hiroshi Mori², and Takuji Shirasawa^{1, 9}

¹ Department of Neurophysiology, Tokyo Metropolitan Institute of Gerontology, Tokyo-173, Japan, ² Department of Molecular Biology, Tokyo Institute for Psychiatry, Tokyo-156, Japan, ³ Research Institute for Biological Science, Science University of Tokyo, Chiba-278, Japan, ⁴ Department of Anatomy, Chiba University, Chiba-260, Japan, ⁵ Department of Neurosurgery, National Center of Neurology and Psychiatry, Tokyo-187, Japan, ⁶ Department of Anatomy, Keio University, Tokyo-160, Japan, ⁷ Department of Veterinary Physiology, Nippon Veterinary and Animal Science University, Tokyo-180, Japan, ⁸ Department of Molecular Immunology, Kyushu University, Fukuoka-812, Japan, and ⁹ CREST, Japan Science and Technology Corporation, Japan

Protein L-isoaspartyl methyltransferase (PIMT) is suggested to play a role in the repair of aged protein spontaneously incorporated with isoaspartyl residues. We generated PIMT-deficient mice by targeted disruption of the PIMT gene to elucidate the biological role of the gene in vivo. PIMT-deficient mice died from progressive epileptic seizures with grand mal and myoclonus between 4 and 12 weeks of age. An anticonvulsive drug, dipropylacetic acid (DPA), improved their survival but failed to cure the fatal outcome. L-Isoaspartatate, the putative substrate for PIMT, was increased ninefold in the brains of PIMT-deficient mice. The brains of PIMT-deficient mice started to enlarge after 4 weeks of age when the apical dendrites of pyramidal neurons in cerebral cortices showed aberrant arborizations with disorganized microtubules. We conclude that methylation of modified proteins with isoaspartyl residues is essential for the maintenance of a mature CNS and that a deficiency in PIMT results in fatal progressive epilepsy in mice.

Key words: protein L-isoaspartyl methyltransferase; gene targeting; isoaspartate; epilepsy; disorganized microtubules; aberrant arborizations

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1862063-12$05.00/0

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