QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) A correction has been published Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (61) Citing Articles via Google Scholar Google Scholar Articles by Yamamoto, A. Articles by Shirasawa, T. Search for Related Content PubMed PubMed Citation Articles by Yamamoto, A. Articles by Shirasawa, T.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				L. Oge, G. Bourdais, J. Bove, B. Collet, B. Godin, F. Granier, J.-P. Boutin, D. Job, M. Jullien, and P. Grappin Protein Repair L-Isoaspartyl Methyltransferase1 Is Involved in Both Seed Longevity and Germination Vigor in Arabidopsis PLANT CELL, November 1, 2008; 20(11): 3022 - 3037. [Abstract] [Full Text] [PDF]

				K. L. Banfield, T. A. Gomez, W. Lee, S. Clarke, and P. L. Larsen Protein-Repair and Hormone-Signaling Pathways Specify Dauer and Adult Longevity and Dauer Development in Caenorhabditis elegans J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2008; 63(8): 798 - 808. [Abstract] [Full Text] [PDF]

				S. J. Weintraub and B. E. Deverman Chronoregulation by Asparagine Deamidation Sci. Signal., October 23, 2007; 2007(409): re7 - re7. [Abstract] [Full Text] [PDF]

				D. Tolleter, M. Jaquinod, C. Mangavel, C. Passirani, P. Saulnier, S. Manon, E. Teyssier, N. Payet, M.-H. Avelange-Macherel, and D. Macherel Structure and Function of a Mitochondrial Late Embryogenesis Abundant Protein Are Revealed by Desiccation PLANT CELL, May 1, 2007; 19(5): 1580 - 1589. [Abstract] [Full Text] [PDF]

				J. X. Zhu, H. A. Doyle, M. J. Mamula, and D. W. Aswad Protein Repair in the Brain, Proteomic Analysis of Endogenous Substrates for Protein L-Isoaspartyl Methyltransferase in Mouse Brain J. Biol. Chem., November 3, 2006; 281(44): 33802 - 33813. [Abstract] [Full Text] [PDF]

				V. Vigneswara, J. D. Lowenson, C. D. Powell, M. Thakur, K. Bailey, S. Clarke, D. E. Ray, and W. G. Carter Proteomic Identification of Novel Substrates of a Protein Isoaspartyl Methyltransferase Repair Enzyme J. Biol. Chem., October 27, 2006; 281(43): 32619 - 32629. [Abstract] [Full Text] [PDF]

				K. J. Reissner, M. V. Paranandi, T. M. Luc, H. A. Doyle, M. J. Mamula, J. D. Lowenson, and D. W. Aswad Synapsin I Is a Major Endogenous Substrate for Protein L-Isoaspartyl Methyltransferase in Mammalian Brain J. Biol. Chem., March 31, 2006; 281(13): 8389 - 8398. [Abstract] [Full Text] [PDF]

				G. W. Young, S. A. Hoofring, M. J. Mamula, H. A. Doyle, G. J. Bunick, Y. Hu, and D. W. Aswad Protein L-Isoaspartyl Methyltransferase Catalyzes in Vivo Racemization of Aspartate-25 in Mammalian Histone H2B J. Biol. Chem., July 15, 2005; 280(28): 26094 - 26098. [Abstract] [Full Text] [PDF]

				Q. Xu, M. P. Belcastro, S. T. Villa, R. D. Dinkins, S. G. Clarke, and A. B. Downie A Second Protein L-Isoaspartyl Methyltransferase Gene in Arabidopsis Produces Two Transcripts Whose Products Are Sequestered in the Nucleus Plant Physiology, September 1, 2004; 136(1): 2652 - 2664. [Abstract] [Full Text] [PDF]

				C. Farrar and S. Clarke Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains of L-Isoaspartyl (D-Aspartyl) O-Methyltransferase-deficient Mice J. Biol. Chem., July 26, 2002; 277(31): 27856 - 27863. [Abstract] [Full Text] [PDF]

				H. Ghandour, B.-F. Lin, S.-W. Choi, J. B Mason, and J. Selhub Folate Status and Age Affect the Accumulation of L-Isoaspartyl Residues in Rat Liver Proteins J. Nutr., June 1, 2002; 132(6): 1357 - 1360. [Abstract] [Full Text] [PDF]

				D. A. Chavous, F. R. Jackson, and C. M. O'Connor Extension of the Drosophila lifespan by overexpression of a protein repair methyltransferase PNAS, December 6, 2001; (2001) 251446498. [Abstract] [Full Text] [PDF]

				D. Kuebler, H. Zhang, X. Ren, and M. A. Tanouye Genetic Suppression of Seizure Susceptibility in Drosophila J Neurophysiol, September 1, 2001; 86(3): 1211 - 1225. [Abstract] [Full Text] [PDF]

				C. F. Fletcher and WayneN. Frankel Ataxic mouse mutantsand molecular mechanisms of absence epilepsy Hum. Mol. Genet., September 1, 1999; 8(10): 1907 - 1912. [Abstract] [Full Text] [PDF]

				E. Kim, J. D. Lowenson, S. Clarke, and S. G. Young Phenotypic Analysis of Seizure-prone Mice Lacking L-Isoaspartate (D-Aspartate) O-Methyltransferase J. Biol. Chem., July 16, 1999; 274(29): 20671 - 20678. [Abstract] [Full Text] [PDF]

				C. L. David, J. Keener, and D. W. Aswad Isoaspartate in Ribosomal Protein S11 of Escherichia coli J. Bacteriol., May 1, 1999; 181(9): 2872 - 2877. [Abstract] [Full Text]

				C. L. David, J. Orpiszewski, X.-C. Zhu, K. J. Reissner, and D. W. Aswad Isoaspartate in Chrondroitin Sulfate Proteoglycans of Mammalian Brain J. Biol. Chem., November 27, 1998; 273(48): 32063 - 32070. [Abstract] [Full Text] [PDF]

				J. D. Lowenson, E. Kim, S. G. Young, and S. Clarke Limited Accumulation of Damaged Proteins in L-Isoaspartyl (D-Aspartyl) O-Methyltransferase-deficient Mice J. Biol. Chem., June 1, 2001; 276(23): 20695 - 20702. [Abstract] [Full Text] [PDF]

				A. L. Young, W. G. Carter, H. A. Doyle, M. J. Mamula, and D. W. Aswad Structural Integrity of Histone H2B in Vivo Requires the Activity of Protein L-Isoaspartate O-Methyltransferase, a Putative Protein Repair Enzyme J. Biol. Chem., September 28, 2001; 276(40): 37161 - 37165. [Abstract] [Full Text] [PDF]

				D. A. Chavous, F. R. Jackson, and C. M. O'Connor Extension of the Drosophila lifespan by overexpression of a protein repair methyltransferase PNAS, December 18, 2001; 98(26): 14814 - 14818. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help