Attenuation of Dopaminergic Neurodegeneration in a C. elegans Parkinson's Model through Regulation of Xanthine Dehydrogenase (XDH-1) Expression by the RNA Editase, ADR-2.

Abstract

Differential RNA editing by adenosine deaminases that act on RNA (ADARs) has been implicated in several neurological disorders, including Parkinson's disease (PD). Here, we report results of a RNAi screen of genes differentially regulated in adr-2 mutants, normally encoding the only catalytically active ADAR in Caenorhabditis elegans, ADR-2. Subsequent analysis of candidate genes that alter the misfolding of human α-synuclein (α-syn) and dopaminergic neurodegeneration, two PD pathologies, reveal that reduced expression of xdh-1, the ortholog of human xanthine dehydrogenase (XDH), is protective against α-synuclein-induced dopaminergic neurodegeneration. Further, RNAi experiments show that WHT-2, the worm ortholog of the human ABCG2 transporter and a predicted interactor of XDH-1, is the rate-limiting factor in the ADR-2, XDH-1, WHT-2 system for dopaminergic neuroprotection. In silico structural modeling of WHT-2 indicates that the editing of one nucleotide in the wht-2 mRNA leads to the substitution of threonine with alanine at residue 124 in the WHT-2 protein, changing hydrogen bonds in this region. Thus, we propose a model where wht-2 is edited by ADR-2, which promotes optimal export of uric acid, a known substrate of WHT-2 and a product of XDH-1 activity. In the absence of editing, uric acid export is limited, provoking a reduction in xdh-1 transcription to limit uric acid production and maintain cellular homeostasis. As a result, elevation of uric acid is protective against dopaminergic neuronal cell death. In turn, increased levels of uric acid are associated with a decrease in ROS production. Further, downregulation of xdh-1 is protective against PD pathologies because decreased levels of XDH-1 correlate to a concomitant reduction in xanthine oxidase (XO), the form of the protein whose by-product is superoxide anion. These data indicate that modifying specific targets of RNA editing may represent a promising therapeutic strategy for PD.