Down-regulation of protein L-isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin.

Full Abstract

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.

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Author information

Author/s: Lanthier, Julie (J); Bouthillier, Alain (A); Lapointe, Marjolaine (M); Demeule, Michel (M); Béliveau, Richard (R); Desrosiers, Richard R (RR);

Affiliation: Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, Hôpital Sainte-Justine, C.P. 8888, Succursale Centre-ville, Montréal, Québec, Canada H3C 3P8.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of neurochemistry (J Neurochem), published in England. (Language: eng)

Reference: 2002-Nov; vol 83 (issue 3) : pp 581-91

Dates: Created 2002/10/22; Completed 2002/11/26; Revised 2006/11/15;

PMID: 12390520, status: MEDLINE (last retrieval date: 11/6/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult
Amino Acid Sequence
Down-Regulation - physiology
Enzyme Activation
Epilepsy, Temporal Lobe - metabolism; pathology
Hippocampus - chemistry; metabolism
Humans
Isoaspartic Acid - analysis; metabolism
Isoenzymes - analysis; metabolism

Mass Spectrometry
Middle Aged
Molecular Sequence Data
Neocortex - chemistry; metabolism
Peptide Fragments - analysis
Protein D-Aspartate-L-Isoaspartate Methyltransferase - analysis; metabolism
Proteins - chemistry; metabolism
Sequence Analysis, Protein
Tubulin - biosynthesis; chemistry

Associated Chemicals: Isoaspartic Acid (0) ; Isoenzymes (0) ; Peptide Fragments (0) ; Proteins (0) ; Tubulin (0) ; Protein D-Aspartate-L-Isoaspartate Methyltransferase (EC 2.1.1.77)

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