Biological significance of isoaspartate and its repair system

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-beta (A beta) peptides in Alzheimer's disease (AD). Specific antibodies recognizing isoaspartate of A beta revealed that isomerized A beta peptides were deposited in senile plaques as well as amyloid-bearing vessels. Moreover, it was revealed that A beta 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 A beta. Furthermore, systematic proline substitution analyses revealed that the beta-turn structure at positions 22 and 23 of A beta 42 plays a crucial role in the aggregation and neurotoxicity of A beta peptides. It is suggested that spontaneous isomerization at position 23 induces the conformational change to form a beta-turn at position 23, which plays a pathogenic role in the deposition of A beta 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.