Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase.
The protein L-isoaspartate (D-aspartate)-O-methyltransferase participates in the repair of age-induced protein damage by initiating the conversion of abnormal aspartyl residues within proteins to normal L-aspartyl residues. Previous studies have shown that mice deficient in the gene encoding this enzyme (Pcmt1-/-) accumulate damaged proteins, have altered levels of brain S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy), and suffer from epileptic seizures that result in death at an average age of about 42 days. In this study, we found that the behavior of Pcmt1-/- mice is abnormal in comparison to their wild-type (Pcmt1+/+) and heterozygous (Pcmt1+/-) littermates in two standard quantitative behavioral assays - the accelerating rotorod and the open-field test. On the accelerating rotorod, we found Pcmt1-/- mice actually perform significantly better than their heterozygous and wild-type littermates, a situation that has only been infrequently described in the literature and has not been described to date for epilepsy-prone mice. The Pcmt1-/- mice show, however, hyperactivity in the open-field test that becomes more pronounced with age, with a partial habituation with time in the chamber. Additionally, these mice demonstrate a strong thigmotaxic movement pattern. We present evidence that these phenotypes are not related to the alterations of the AdoMet/AdoHcy ratio in the brain and thus may be a function of the accumulation of damaged proteins. These results implicate a role for this enzyme in motor coordination and cerebellum development and suggest the importance of the function of the repair methyltransferase in hippocampal-dependent spatial learning.
Vitali
Ryan
R
Department of Chemistry and Biochemistry, Molecular Biology Institute, UCLA, 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569, USA.
Clarke
Steven
S
D000367:Age Factors; D000375:Aging / Q000502:physiology; D000818:Animals; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004038:Diet, Reducing / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology*; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006948:Hyperkinesis; D051379:Mice; D018345:Mice, Knockout; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D045442:Rotarod Performance Test; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013239:Stereotyped Behavior / Q000502:physiology; D015996:Survival Rate; D013997:Time Factors
D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase