Aging and post-translational modification of aspartates in proteins

点击翻译按钮获取中文摘要

Protein-L-isoaspartyl methyltransfearase (PIMT) plays a physiological role in the repair of damaged proteins containing isoaspartyl residues (IsoAsp). In previous studies, we showed that PIMT-deficient mice developed a fatal epileptic seizure associated with the accumulation of damaged proteins in the brain. In the present study, we generated PIMT transgenic (Tg) mice to investigate whether the exogenous expression of PIMT could improve the symptoms associated with PIMT-deficiency. Rescue experiments showed that Tg expression of PIMT effectively cured the PIMT-deficient mice. Biochemically, a higher expression level of transgene led to the effective repair of damaged proteins in vivo. Although a lower level of expression caused an accumulation of damaged proteins in a partially-rescued line, the mice survived. Furthermore, We administered an adeno-PIMT vector into the brain of PIMT-deficient mice at embryonic day 14.5 by an exoutero method to assess the biological effects in vivo. The result showed that adeno-PIMT improved the symptoms of PIMT-deficient mice in vivo, but only partially repaired IsoAsp in damaged proteins. The gene therapy presented in this report provided a better prognosis for the survival of PIMT-deficient mice than the previously reported anti-epileptic drug therapy.