Biological Significance of Isoaspartate and Its Repair System(D-Amino Acid Biosystem)

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概要

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• Isomerization of L-aspartate and deamidation of L-asparagine in proteins or peptides dominantly give rise to L-isoaspartate by a non-enzymatic reaction via succinimide as a intermediate under physiological conditions. Isoaspartates have been identified in a variety of cellular proteins in vivo as well as pathologically deposited proteins in neurodegenerative brain tissue. We described here that the formation of isoaspartate is enhanced in amyloid-β(Aβ) peptides in Alzheimer's disease (AD). Specific antibodies recognizing isoaspartate of Aβ revealed that isomerized Aβ peptides were deposited in senile plaques as well as amyloid-bearing vessels. Moreover, it was revealed that Aβ peptides, isomerized at position 7 or 23, were differentially deposited in senile plaques and vascular amyloids in AD brains. In vitro experiments showed that the modification at position 23 greatly enhanced the aggregation of Aβ. Furthermore, systematic proline substitution analyses revealed that the β-turn structure at positions 22 and 23 of Aβ42 plays a crucial role in the aggregation and neurotoxicity of Aβ peptides. It is suggested that spontaneous isomerization at position 23 induces the conformational change to form a β-turn at position 23, which plays a pathogenic role in the deposition of Aβ peptides in sporadic AD. Protein L-isoaspartyl methyltransferase (PIMT) is a putative protein repair enzyme, which converts L-isoaspartyl residues in damaged proteins to normal L-aspartyl residues. PIMT-deficient mice manifested neurodegenerative changes concomitant with the accumulation of L-isoaspartate in the brain. We discuss here the pathological implications of the formation of isoaspartate in damaged proteins during neurodegeneration in model mice and AD.

• 2005-09-01

著者

• SHIMIZU Takahiko

  Research Team for Molecular Biomarkers, Tokyo Metropolitan Istitute of Gerontology

• SHIRASAWA Takuji

  Research Team for Molecular Biomarkers, Tokyo Metropolitan Istitute of Gerontology

• Shimizu Takahiko

  Research Team For Molecular Biomarkers Tokyo Metropolitan Institute Of Gerontology

• Shirasawa Takuji

  Research Group Of Molecular Gerontology Tokyo Metropolitan Institute Of Gerontology

• MATSUOKA Yasuji

  Center for Dementia Research, Nathan Kline Institute for Psychiatric Research and Department of Psyc

• Matsuoka Yasuji

  Center For Dementia Research Nathan Kline Institute For Psychiatric Research And Department Of Psych

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