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

Abstract

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.

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

“…These mice exhibited slow growth and a fatal seizure disorder leading to death after an average of 42 days of age (Kim et al 1997(Kim et al , 1999Yamamoto et al 1998). In addition, PIMT-/-mice showed aberrant synaptic transmission in the CA3 region of the hippocampus, associated with an abnormal distribution of synaptic vesicles in the mossy fiber terminals (Ikegaya et al 2001).…”

“…It has been previously reported that PIMT activity is important for the maintenance of the central nervous system since PIMT-deficient mice died from progressive epileptic seizures and showed aberrant synaptic transmission in the hippocampus (Kim et al 1997(Kim et al , 1999Yamamoto et al 1998;Ikegaya et al 2001). This suggests that changes in PIMT activity in the human brain during epilepsy, particularly in the hippocampus which is the major seat of temporal lobe epilepsy, may be involved in this disease.…”

“…Accumulation of abnormal aspartyl residues in tubulin in epileptic hippocampus The brain size of PIMT-/-mice is larger than that of PIMT+/+ animals and contains pyramidal neurons with deformed dendrites, which are associated with disorganized microtubules (Yamamoto et al 1998). Since tubulin aspartyl isomerization could be a mechanism for microtubule disorganization in neurons, we sought to investigate the accumulation of L-isoaspartyl residues in tubulin, which has been reported to be an in vivo and in vitro substrate for PIMT (Ohta et al 1987;Najbauer et al 1996).…”

“…These mice showed an accumulation of damaged aspartyl residues in all tissues, particularly in the brain (Kim et al 1997). Such knockout mice (PIMT-/-) also showed significantly slower growth as well as premature death, caused by fatal generalized seizures characteristic of fatal progressive epilepsy (Kim et al 1997(Kim et al , 1999Yamamoto et al 1998). Also, these PIMT-/-mice show aberrant neurotransmission in the synapses of mossy fibers in the CA3 region of the hippocampus, associated with an atypical distribution of synaptic vesicles, abnormal microtubule organization in the dendrites of pyramidal neurons and vacuolar degeneration (Yamamoto et al 1998;Ikegaya et al 2001).…”

“…Such knockout mice (PIMT-/-) also showed significantly slower growth as well as premature death, caused by fatal generalized seizures characteristic of fatal progressive epilepsy (Kim et al 1997(Kim et al , 1999Yamamoto et al 1998). Also, these PIMT-/-mice show aberrant neurotransmission in the synapses of mossy fibers in the CA3 region of the hippocampus, associated with an atypical distribution of synaptic vesicles, abnormal microtubule organization in the dendrites of pyramidal neurons and vacuolar degeneration (Yamamoto et al 1998;Ikegaya et al 2001). These results raised the hypothesis that PIMT is essential for the maintenance of the central nervous system, especially the hippocampus, and that a deficiency in this repair enzyme induces progressive epilepsy in mice (Ikegaya et al 2001).…”