Accelerated protein damage in brains of PIMT plus /-mice; a possible model for the variability of cognitive decline in human aging

作者：Qin Zhenxia; Dimitrijevic Aleksandra; Aswad Dana W^*

来源：Neurobiology of Aging, 2015, 36(2): 1029-1036.

DOI：10.1016/j.neurobiolaging.2014.10.036

• Creatine kinase
• Deamidation
• Isoaspartate
• Methyltransferase
• Protein damage
• Protein repair

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 5x faster in HZ males and 3x 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.

• 出版日期2015-2