| http://purl.uniprot.org/citations/35764292 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/35764292 | http://www.w3.org/2000/01/rdf-schema#comment | "IntroductionMitochondrial defects have been implicated in Parkinson's disease (PD) since complex I poisons were found to cause accelerated parkinsonism in young people in the early 1980s. More evidence of mitochondrial involvement arose when many of the genes whose mutations caused inherited PD were discovered to be subcellularly localized to mitochondria or have mitochondrial functions. However, the details of how mitochondrial dysfunction might impact or cause PD remain unclear. The aim of our study was to better understand mitochondrial dysfunction in PD by evaluating mitochondrial respiratory complex mutations in a Drosophila melanogaster (fruit fly) model of PD.MethodsWe have conducted a targeted heterozygous enhancer/suppressor screen using Drosophila mutations within mitochondrial electron transport chain (ETC) genes against a null PD mutation in parkin. The interactions were assessed by climbing assays at 2-5 days as an indicator of motor function. A strong enhancer mutation in COX5A was examined further for L-dopa rescue, oxygen consumption, mitochondrial content, and reactive oxygen species. A later timepoint of 16-20 days was also investigated for both COX5A and a suppressor mutation in cyclope. Generalized Linear Models and similar statistical tests were used to verify significance of the findings.ResultsWe have discovered that mutations in individual genes for subunits within the mitochondrial respiratory complexes have interactions with parkin, while others do not, irrespective of complex. One intriguing mutation in a complex IV subunit (cyclope) shows a suppressor rescue effect at early time points, improving the gross motor defects caused by the PD mutation, providing a strong candidate for drug discovery. Most mutations, however, show varying degrees of enhancement or slight suppression of the PD phenotypes. Thus, individual mitochondrial mutations within different oxidative phosphorylation complexes have different interactions with PD with regard to degree and direction. Upon further investigation of the strongest enhancer (COX5A), the mechanism by which these interactions occur initially does not appear to be based on defects in ATP production, but rather may be related to increased levels of reactive oxygen species.ConclusionsOur work highlights some key subunits potentially involved in mechanisms underlying PD pathogenesis, implicating ETC complexes other than complex I in PD."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.nbd.2022.105803"xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/author | "Sanz A."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/author | "Scialo F."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/author | "Bass R."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/author | "Smulders-Srinivasan T.K."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/author | "Tweedy C."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/author | "O'Hanlon M.E."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/date | "2022"xsd:gYear |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/name | "Neurobiol Dis"xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/pages | "105803"xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/title | "Mitochondrial electron transport chain defects modify Parkinson's disease phenotypes in a Drosophila model."xsd:string |
| http://purl.uniprot.org/citations/35764292 | http://purl.uniprot.org/core/volume | "171"xsd:string |
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