| Autor: |
Starr LA; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA., McKay LE; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA., Peter KN; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA., Seyfarth LM; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA., Berkowitz LA; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA., Caldwell KA; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA.; Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center of Excellence for the Basic Biology of Aging, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Caldwell GA; Department of Biological Sciences, Center for Convergent Biomedicine, Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35487, USA.; Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center of Excellence for the Basic Biology of Aging, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. |
| Abstrakt: |
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. |
