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Diet-dependent survival of protein repair-deficient mice
Christine E Farrar1, Steven Clarke
1Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095, USA.
Abstract:
Protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) is a protein-repair enzyme, and mice lacking this enzyme accumulate damaged proteins in multiple tissues, die at an early age from progressive epilepsy and have an increased S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy) ratio in brain tissue. It has been proposed that the alteration of AdoMet and AdoHcy levels might contribute to the seizure phenotype, particularly as AdoHcy has anticonvulsant properties. To investigate whether altered AdoMet and AdoHcy levels might contribute to the seizures and thus the survivability of the repair-deficient mice, a folate-deficient amino acid-based diet was administered to the mice in place of a standard chow diet. We found that the low-folate diet significantly decreases the AdoMet/AdoHcy ratio in brain tissue and results in an almost threefold extension of mean life span in the protein repair-deficient mice. These results indicate that the increased AdoMet/AdoHcy ratio may contribute to the lowered seizure threshold in young PCMT1-deficient mice. However, mean survival was also extended almost twofold for mice on a control folate-replete amino acid-based diet compared to mice on the standard chow diet. Survival after 40 days was similar in the mice on the low- and high-folate amino acid-based diets, suggesting that the survival of older PCMT1-deficient mice is not affected by the higher brain AdoMet/AdoHcy ratio. Additionally, the surviving older repair-deficient mice have a significant increase in body weight when compared to age-matched normal mice, independent of the type of diet. This weight increase was not accompanied by an increase in consumption levels, indicating that the repair-deficient mice may also have an altered metabolic state.
Insights
Protein L-isoaspartyl O-methyltransferase (PCMT1) deficiency causes early death and seizures in mice. A low-folate diet extended lifespan by reducing the brain S-adenosylmethionine to S-adenosylhomocysteine ratio, suggesting this ratio impacts survival.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) is crucial for protein repair.
- PCMT1-deficient mice exhibit protein damage, premature death, epilepsy, and altered brain S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy) ratios.
- AdoHcy's anticonvulsant properties suggest altered AdoMet/AdoHcy levels may influence seizure susceptibility.
Purpose of the Study:
- To investigate the role of altered AdoMet/AdoHcy levels in seizures and survival of PCMT1-deficient mice.
- To determine if dietary folate manipulation can impact the AdoMet/AdoHcy ratio and survival in these mice.
Main Methods:
- PCMT1-deficient mice were fed either a standard chow diet, a folate-replete amino acid-based diet, or a folate-deficient amino acid-based diet.
- Brain AdoMet/AdoHcy ratios and animal survival rates were measured.
- Body weight and food consumption were monitored in surviving mice.
Main Results:
- A low-folate diet significantly decreased brain AdoMet/AdoHcy ratios and extended mean lifespan by nearly threefold in PCMT1-deficient mice.
- A folate-replete amino acid diet also extended survival compared to standard chow, though less than the low-folate diet.
- Survival beyond 40 days was similar across diets, indicating older mice are less affected by high AdoMet/AdoHcy ratios.
- Surviving older PCMT1-deficient mice showed increased body weight independent of diet, suggesting altered metabolism.
Conclusions:
- Elevated brain AdoMet/AdoHcy ratios may contribute to a lower seizure threshold in young PCMT1-deficient mice.
- Dietary folate influences lifespan in PCMT1-deficient mice, likely through modulation of the AdoMet/AdoHcy ratio.
- PCMT1 deficiency is associated with altered metabolism and increased body weight in older mice, irrespective of diet.
