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

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dc.contributor.authorStarr, Lindsey A.
dc.contributor.authorMcKay, Luke E.
dc.contributor.authorPeter, Kylie N.
dc.contributor.authorSeyfarth, Lena M.
dc.contributor.authorBerkowitz, Laura A.
dc.contributor.authorCaldwell, Kim A.
dc.contributor.authorCaldwell, Guy A.
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherUniversity of Alabama Birmingham
dc.date.accessioned2023-09-29T12:44:57Z
dc.date.available2023-09-29T12:44:57Z
dc.date.issued2023
dc.description.abstractDifferential 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 alpha-synuclein (alpha-syn) and dopaminergic neurodegeneration, two PD pathologies, reveal that reduced expression of xdh-1, the ortholog of human xanthine dehydrogenase (XDH), is protective against alpha-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.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationStarr, L. A., McKay, L. E., Peter, K. N., Seyfarth, L. M., Berkowitz, L. A., Caldwell, K. A., & Caldwell, G. A. (2023). 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. In Journal of Developmental Biology (Vol. 11, Issue 2, p. 20). MDPI AG. https://doi.org/10.3390/jdb11020020
dc.identifier.doi10.3390/jdb11020020
dc.identifier.orcidhttps://orcid.org/0000-0002-0965-2844
dc.identifier.orcidhttps://orcid.org/0000-0003-1580-6122
dc.identifier.orcidhttps://orcid.org/0009-0000-1261-8703
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12355
dc.languageEnglish
dc.language.isoen_US
dc.publisherMDPI
dc.subjectABC transporter
dc.subjectalpha-synuclein
dc.subjectADAR
dc.subjectC. elegans
dc.subjectdopamine
dc.subjectneurodegeneration
dc.subjectParkinson's disease
dc.subjectRNA editing
dc.subjectxanthine dehydrogenase
dc.subjectMESSENGER-RNA
dc.subjectCAENORHABDITIS-ELEGANS
dc.subjectTRANSCRIPT STABILITY
dc.subjectCOMPLEX-I
dc.subjectDISEASE
dc.subjectBRAIN
dc.subjectGENE
dc.subjectTRANSPORTERS
dc.subjectOXIDASE
dc.subjectBINDING
dc.subjectDevelopmental Biology
dc.titleAttenuation of Dopaminergic Neurodegeneration in a C. elegans Parkinson's Model through Regulation of Xanthine Dehydrogenase (XDH-1) Expression by the RNA Editase, ADR-2en_US
dc.typeArticle
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