Mice hemizygous for the human aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) transgene are viable and fertile. Expression of the transgene is regulated by the tetracycline operator (tetO); also called tetracycline-responsive element (TRE, TetRE) or tet-operator). AIMP2 is a substrate of PARKIN (PARK2), an E3 ligase expressed in the brain that ubiquitinates damaged and excess proteins, marking them for degradation and clearance by proteasomes. Mutations of PARK have been implicated in the onset of Parkinson's disease, allowing pathogenic substrates, such as AIMP2, to accumulate. The buildup of these proteins disrupts normal cell activities, and impairs nerve cells, including dopamine-producing nerve cells. When mated to a strain expressing tetracycline-controlled transactivator protein (tTA), expression of the AIMP2 protein may be regulated with tetracycline or its analog doxycycline (dox) in the double mutant offspring.
For example, when mice from this founder line (630) are bred to B6.Cg-Tg(Camk2a-tTA)1Mmay/DboJ mice (Stock No. 007004) expressing tTA in forebrain neurons, double mutant offspring overexpress AIMP2 14-fold in neurons of the cortex and 4-fold in neurons of the ventral midbrain after. These mice exhibit progressive loss of 28% of their dopaminergic neurons in the ventral tegmental area by 20 months of age. They also exhibited progressive loss of neurons in the substantia nigra zona compacta, reaching 53% by 20 months of age. Mice from founder line 630 have higher AIMP2 expression in neurons of the cortex than mice from founder line 634 (Stock No. 023642).
