Down-regulation of protein L-isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin.
Protein L-isoaspartyl methyltransferase (PIMT) repairs the damaged proteins which have accumulated abnormal aspartyl residues during cell aging. Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures. Here we investigated the role of PIMT in human mesial temporal lobe epilepsy. Using surgical specimens of hippocampus and neocortex from controls and epileptic patients, we showed that PIMT activity and expression were 50% lower in epileptic hippocampus than in controls but were unchanged in neocortex. Although the protein was down-regulated, PIMT mRNA expression was unchanged in epileptic hippocampus, suggesting post-translational regulation of the PIMT level. Moreover, several proteins with abnormal aspartyl residues accumulate in epileptic hippocampus. Microtubules component beta-tubulin, one of the major PIMT substrates, had an increased amount (two-fold) of L-isoaspartyl residues in the epileptic hippocampus. These results demonstrate that the down-regulation of PIMT in epileptic hippocampus leads to a significant accumulation of damaged tubulin that could contribute to neuron dysfunction in human mesial temporal lobe epilepsy.
Lanthier
Julie
J
Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, Hôpital Sainte-Justine, C.P. 8888, Succursale Centre-ville, Montréal, Québec, Canada H3C 3P8.
Bouthillier
Alain
A
Lapointe
Marjolaine
M
Demeule
Michel
M
Béliveau
Richard
R
Desrosiers
Richard R
RR
D000328:Adult; D000595:Amino Acid Sequence; D015536:Down-Regulation / Q000502:physiology*; D004789:Enzyme Activation; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D026581:Isoaspartic Acid / Q000032:analysis / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D013058:Mass Spectrometry; D008875:Middle Aged; D008969:Molecular Sequence Data; D019579:Neocortex / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000032:analysis / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D020539:Sequence Analysis, Protein; D014404:Tubulin / Q000096:biosynthesis* / Q000737:chemistry
D026581:Isoaspartic Acid; D007527:Isoenzymes; D010446:Peptide Fragments; D011506:Proteins; D014404:Tubulin; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase