Bi-phasic regulation of AIMP2 and its splice variant in PARP-1- dependent neurodegeneration

Abstract

Parthanatos is a significant molecular cause of Parkinsons disease, in which AIMP2 aberrantly activates PARP-1 through a physical interaction. Interestingly, AIMP2 has an antagonistic splice variant, named DX2, which compromises AIMP2-induced apoptosis via p53 or inflammatory pathway. Here we suggested that DX2 binds to PARP-1 with a higher affinity than AIMP2, deactivating it and improving synaptic physiology. To deliver DX2 into deep brain areas, miR142 target sequence-embedded adeno-associated virus was designed to avoid unexpected expression in hematopoietic cells. RNAseq analysis revealed that DX2 selectively suppressed cell death-associated pathways, such as p53 and neuroinflammation. Upon a single intracranial injection, both behaviour and motility were mitigated in three animal models of Parkinsonism, induced by MPTP, rotenone, or 6-OHDA. Efficacy was observed in therapeutic model as well as preventive ones. Thus, AIMP2 and DX2 are suggested to act as an ON/OFF switch for PARP-1. In particular, as cell survival properties of DX2 was exerted only when AIMP2 is accumulated abnormally, without its own additional tumorigenicity, DX2 could be a unique therapeutic tool for treating patients with Parkinsons disease.