Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Farrar, Christine; Clarke, Steven

doi:10.1074/jbc.m203911200

Cited by 32 publications

(34 citation statements)

References 50 publications

(60 reference statements)

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“…Tubulin [18], synapsin 1 [25], and amyloid-beta peptide [24,28] have all been identified as potential candidates for isoaspartyl accumulation leading to loss of function. However, the loss of the repair enzyme has also been shown to alter the concentrations in brain of its small molecule substrates AdoMet and S-adenosyl-l-homocysteine (AdoHcy) [5]. It is thus possible that the increased AdoMet/AdoHcy ratio that accompanies the loss of Pcmt1 may also contribute to the Pcmt1−/− mutant seizure phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…High pressure liquid chromatography analysis of AdoMet and AdoHcy levels in whole mouse brain homogenates were done of mice sacrificed at 50 days of age by a previously described protocol [5].…”

Section: Mouse Brain Hplc Analysismentioning

confidence: 99%

“…This en-edly display a phenotype of progressive epilepsy resulting in their death at an average of 42 days of age [5,15,16,30]. EEG analysis revealed that Pcmt1−/− mice display abnormal electrical activity approximately 50% of the time monitored, even when they are not overtly seizing [15].…”

Section: Introductionmentioning

confidence: 99%

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Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase

Vitali¹,

Clarke²

2004

Behavioural Brain Research

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Mouse Brain Hplc Analysismentioning

confidence: 99%

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Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase

Vitali¹,

Clarke²

2004

Behavioural Brain Research

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“…PIMT is known to protect certain neural cells from Bax-induced apoptosis through an SAM-binding motif-dependent mechanism (Huebscher et al 1999) and to repair abnormal proteins to maintain normal mitogen-activated protein kinase (MAPK) signaling (Kosugi et al 2008). Pcmt1 null (pcmt1(-/-)) mice present with significantly higher levels of SAM and lower levels of S-adenosylhomocysteine (SAH) in their brains compared with their wild-type littermates (Farrar and Clarke 2002). They accumulate Lisoaspartyl residues in several tissues and die, on average, 42 days after birth from progressive epileptic seizures (Kim et al 1997).…”

Section: Introductionmentioning

confidence: 99%

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

Wang

Guo

et al. 2013

Genes Nutr

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The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 lmol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG ? GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant.

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“…When this gene is ablated in gene targeting studies, nullizygous Pcmt1 knockout mice suffer from epileptic seizures that result in the animal's death at an average of 42 days of age [7]. Farrar and Clarke [8] measured metabolites, including AdoMet and AdoHcy in the brains of Pcmt1 nullizygotes, Pcmt1 heterozygotes, and wildtype mice. Highest levels of AdoMet and lower levels of AdoHcy were found in the brains of Pcmt1 null mice, and to a lesser extent, in the heterozygous mice, when compared with wildtype mice.…”

Section: Introductionmentioning

confidence: 99%

A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida

Zhu

Yang²,

Lü

et al. 2006

Molecular Genetics and Metabolism

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Folate binding protein 1 (Folr1) knockout mice with low maternal folate concentrations have been shown to be excellent animal models for human folate-responsive neural tube defects (NTDs). Previous studies using the Folr1 knockout mice revealed that maternal folate supplementation upregulates the expression of the PCMT1 gene in Folr1 nullizygous neural tube tissue during neural tube closure. PCMT1 encodes the protein repair enzyme L-isoaspartate (D-aspartate) Omethyltransferase (PIMT) that converts abnormal D-aspartyl and L-isoaspartyl residues to the normal L-aspartyl form. PIMT is known to protect certain neural cells from Bax-induced apoptosis. Pcmt1-deficient mice present with abnormal AdoMet/AdoHcy homeostasis. We hypothesized that a known functional polymorphism (Ile120Val) in the human PCMT1 gene is associated with an increased risk of folate-responsive human NTDs. A case-control study was conducted to investigate a possible association between this polymorphism and risk of spina bifida. Compared to the Ile/Ile and Ile/Val genotypes, the homozygous Val/Val genotype showed decreased risk for spina bifida (adjusted odds ratio = 0.6, 95% confidence interval: 0.4-0.9). Our results showed that the Ile120Val polymorphism of PCMT1 gene is a genetic modifier for the risk of spina bifida. Val/Val genotype was associated with a reduction in risk for spina bifida.

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Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Cited by 32 publications

References 50 publications

Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase

Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida

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