Poly (ADP-ribose) in the pathogenesis of Parkinson's disease

Abstract

The defining feature of Parkinson's disease is a progressive and selective demise of dopaminergic neurons. A recent report on Parkinson's disease animal model demonstrates that poly (ADP-ribose) (PAR) dependent cell death, also named parthanatos, is accountable for selective dopaminergic neuronal loss. Parthanatos is a programmed necrotic cell death, characterized by PARP1 activation, apoptosis inducing factor (AIF) nuclear translocation, and large scale DNA fragmentation. Besides cell death regulation via interaction with AIF, PAR molecule mediates diverse cellular processes including genomic stability, cell division, transcription, epigenetic regulation, and stress granule formation. In this review, we will discuss the roles of PARP1 activation and PAR molecules in the pathological processes of Parkinson's disease. Potential interaction between PAR molecule and Parkinson's disease protein interactome are briefly introduced. Finally, we suggest promising points of therapeutic intervention in the pathological PAR signaling cascade to halt progression in Parkinson's disease.

Fig. 1.. Illustration of potential involvement of PAR in the pathophysiology of PD. Excessive PAR synthesis can cause cell death via release of mitochondrial AIF. Subsequent nuclear translocation of AIF is responsible for PAR dependent cell death, or parthanatos. PAR is synthesized in response to PARP1 overactivation. In PD animal models, mitochondrial toxins can lead to calcium influx which is induced by energy imbalance and glutamate release. Intracellular calcium activates nitric oxide (NO) synthase which produces NO. The NO reacts with reactive oxygen species and is converted to peroxynitrite, a potent DNA damaging reagent. DNA damage can stimulate PARP1 activation, leading to dopamine cell loss. Even in the absence of DNA damage, E3 ubiquitin ligase parkin dysfunction and resulting accumulation of the substrate AIMP2 can also enhance PARP1 activity via direct binding. PAR overproduction may affect not only the AIF mediated cell death, but other cellular functions as well, by its interaction with proteins containing the PAR binding motif.

Fig. 2.. Gene ontology analysis of PAR and PD protein interactome. By using Cytoscape ClueGo, each common interactor in the Table 1 was functionally annotated. Functional annotations which are highlighted by at least three proteins are presented.