Limited accumulation of damaged proteins in L-isoaspartyl (D-aspartyl) O-methyltransferase-deficient mice

L-Isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) can initiate the con version of damaged aspartyl and asparaginyl residues to normal L-aspartyl r esidues. Mice lacking this enzyme (Pcmt1-/- mice) have elevated levels of d amaged residues and die at a mean age of 42 days from massive tonic-clonic seizures. To extend the lives of the knockout mice so that the long term ef fects of damaged residue accumulation could be investigated, we produced tr ansgenic mice with a mouse Pcmt1 cDNA under the control of a neuron specifi c promoter. Pcmt1 transgenic mice that were homozygous for the endogenous P cmt1 knockout mutation ("transgenic Pcmt1-/- mice") had brain PCMT1 activit y levels that were 6.5-13% those of mild-type mice but had little or no act ivity in other tissues. The transgenic Pcmt1-/- mice lived, on average, B-f old longer than nontransgenic Pcmt1-/- mice and accumulated only half as ma ny damaged aspartyl residues in their brain proteins. The concentration of damaged residues in heart, testis, and brain proteins in transgenic Pcmt1-/ - mice initially increased with age but unexpectedly reached a plateau by 1 00 days of age. Urine from Pcmt1-/- mice contained increased amounts of pep tides with damaged aspartyl residues, apparently enough to account for prot eins that were not repaired intracellularly. In the absence of PCMT1, prote olysis may limit the intracellular accumulation of damaged proteins but les s efficiently than in wild-type mice having PCMT1-mediated repair.