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  1. Article ; Online: Attenuation of Dopaminergic Neurodegeneration in a

    Starr, Lindsey A / McKay, Luke E / Peter, Kylie N / Seyfarth, Lena M / Berkowitz, Laura A / Caldwell, Kim A / Caldwell, Guy A

    Journal of developmental biology

    2023  Volume 11, Issue 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 ... ...

    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
    Language English
    Publishing date 2023-05-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720870-9
    ISSN 2221-3759 ; 2221-3759
    ISSN (online) 2221-3759
    ISSN 2221-3759
    DOI 10.3390/jdb11020020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: 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

    Starr, Lindsey A. / McKay, Luke E. / Peter, Kylie N. / Seyfarth, Lena M. / Berkowitz, Laura A. / Caldwell, Kim A. / Caldwell, Guy A.

    J Dev Biol. 2023 May 22, v. 11, no. 2

    2023  

    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 ... ...

    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.
    Keywords Caenorhabditis elegans ; RNA ; adenosine deaminase ; alanine ; byproducts ; cell death ; computer simulation ; exports ; homeostasis ; humans ; hydrogen ; models ; neurodegenerative diseases ; neurons ; neuroprotective effect ; superoxide anion ; therapeutics ; threonine ; uric acid ; xanthine dehydrogenase ; xanthine oxidase
    Language English
    Dates of publication 2023-0522
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article ; Online
    ZDB-ID 2720870-9
    ISSN 2221-3759
    ISSN 2221-3759
    DOI 10.3390/jdb11020020
    Database NAL-Catalogue (AGRICOLA)

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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