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Updated: Aug 7, 2026
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Published on: May 18, 2010
Accelerated protein damage in brains of PIMT+/- mice; a possible model for the variability of cognitive decline in
Zhenxia Qin1, Aleksandra Dimitrijevic1, Dana W Aswad1
1Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA.
Abstract:
Isoaspartate formation is a common type of protein damage normally kept in check by the repair enzyme protein-L-isoaspartyl methyltransferase (PIMT). Mice with a knockout of the gene (Pcmt1) for this enzyme (KO, -/-) exhibit a pronounced neuropathology with fatal epileptic seizures at 30-60 days. Heterozygous (HZ, +/-) mice have 50% of the PIMT activity found in wild-type (WT, +/+) mice, but appear normal. To see if HZ mice exhibit accelerated aging at the molecular level, we compared brain extracts from HZ and WT mice at 8 months and 2 years with regard to PIMT activity, isoaspartate levels, and activity of an endogenous PIMT substrate, creatine kinase B. PIMT activity declined modestly with age in both genotypes. Isoaspartate was significantly higher in HZ than WT mice at 8 months and more so at 2 years, rising 5× faster in HZ males and 3× faster in females. Creatine kinase activity decreased with age and was always lower in the HZ mice. These findings suggest the individual variation of human PIMT levels may significantly influence the course of age-related central nervous system dysfunction.
Insights
Reduced protein repair enzyme (PIMT) activity in mice leads to accelerated brain aging and increased damage. This suggests human PIMT levels may impact age-related neurological decline.
Area of Science:
- Biochemistry
- Neuroscience
- Aging Research
Background:
- Isoaspartate formation is a common protein damage mechanism.
- Protein-L-isoaspartyl methyltransferase (PIMT) repairs this damage.
- Mice lacking PIMT (KO) show severe neuropathology and seizures.
Purpose of the Study:
- To investigate if heterozygous (HZ) mice, with 50% PIMT activity, exhibit molecular signs of accelerated aging.
- To assess the impact of reduced PIMT on brain health over time.
Main Methods:
- Compared brain extracts from HZ and wild-type (WT) mice at 8 months and 2 years.
- Measured PIMT activity, isoaspartate levels, and creatine kinase B activity.
Main Results:
- PIMT activity decreased with age in both genotypes.
- Isoaspartate levels were significantly higher in HZ mice, increasing faster with age.
- Creatine kinase B activity decreased with age and was lower in HZ mice.
Conclusions:
- Reduced PIMT activity in HZ mice correlates with molecular markers of accelerated brain aging.
- Individual variations in human PIMT levels may influence age-related central nervous system dysfunction.
