{"doi":"10.3390/jdb11020020","title":"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.","journal":"Journal of Developmental Biology","year":2023,"id":352612,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9476,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":911042,"name":"Luke E. McKay","orcid":"0000-0002-3601-635X","position":1,"is_corresponding":false},{"id":1098930,"name":"Kylie N. Peter","orcid":null,"position":2,"is_corresponding":false},{"id":1085597,"name":"Lena M. Seyfarth","orcid":"0000-0002-0965-2844","position":3,"is_corresponding":false},{"id":911722,"name":"Laura A. Berkowitz","orcid":null,"position":4,"is_corresponding":false},{"id":257435,"name":"Kim A. Caldwell","orcid":"0000-0003-1580-6122","position":5,"is_corresponding":false},{"id":257437,"name":"Guy A. Caldwell","orcid":"0000-0002-8283-9090","position":6,"is_corresponding":false},{"id":1098459,"name":"Lindsey A. Starr","orcid":"0009-0000-1261-8703","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37218814","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}