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Differential effects of loss of park7 activity on Iron Responsive Element (IRE) gene sets: Implications for the role of iron dyshomeostasis in the pathophysiology of Parkinson’s disease

Hui Yung Chin, View ORCID ProfileMichael Lardelli, View ORCID ProfileLyndsey Collins-Praino, View ORCID ProfileKarissa Barthelson
doi: https://doi.org/10.1101/2021.03.25.437102
Hui Yung Chin
1Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SΛ 5005, Australia
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Michael Lardelli
1Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SΛ 5005, Australia
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Lyndsey Collins-Praino
2Department of Biomedical Sciences, Adelaide Medical School, University of Adelaide, Frome Rd Adelaide SA 5005, Australia
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Karissa Barthelson
1Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SΛ 5005, Australia
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  • ORCID record for Karissa Barthelson
  • For correspondence: karissa.barthelson@adelaide.edu.au
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Abstract

Mutation of the gene PARK7 (DJ1) causes monogenic autosomal recessive Parkinson’s disease (PD) in humans. Subsequent alterations of PARK7 protein function lead to mitochondrial dysfunction, a major element in PD pathology. Homozygous mutants for the PARK7-orthologous genes in zebrafish, park7, show changes to gene expression in the oxidative phosphorylation pathway, supporting that disruption of energy production is a key feature of neurodegeneration in PD. Iron is critical for normal mitochondrial function, and we have previously used bioinformatic analysis of IRE-bearing transcripts in brain transcriptomes to find evidence supporting the existence of iron dyshomeostasis in Alzheimer’s disease. Here, we analysed IRE-bearing transcripts in the transcriptome data from homozygous park7−/− mutant zebrafish brains. We found that the set of genes with “high quality” IREs in their 5’ untranslated regions (UTRs, the HQ5’IRE gene set) was significantly altered in these 4-month-old park7−/− brains. However, sets of genes with IREs in their 3’ UTRs appeared unaffected. The effects on HQ5’IRE genes are possibly driven by iron dyshomeostasis and/or oxidative stress, but illuminate the existence of currently unknown mechanisms with differential overall effects on 5’ and 3’ IREs.

Competing Interest Statement

The authors have declared no competing interest.

  • List of abbreviations

    PD
    Parkinson’s disease
    IRE
    Iron responsive element
    HQ
    High quality
    UTRs
    untranslated
    GSH
    glutathione
    SNc DA
    substantia nigra pars compacta dopaminergic neurons
    ETC
    Electron transport chain
    ROS
    Reactive oxygen species
    IRP1
    Iron regulatory proteins 1
    IRP2
    Iron regulatory proteins 2
    mRNA
    Messenger ribonucleic acid
    AD
    Alzheimer’s disease
    RNA-seq
    RNA sequencing
    GSEA
    gene set enrichment analysis
    alas 2
    Delta-aminolevulinate synthase 2
    FDR
    false discovery rate
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    Posted March 27, 2021.
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    Differential effects of loss of park7 activity on Iron Responsive Element (IRE) gene sets: Implications for the role of iron dyshomeostasis in the pathophysiology of Parkinson’s disease
    Hui Yung Chin, Michael Lardelli, Lyndsey Collins-Praino, Karissa Barthelson
    bioRxiv 2021.03.25.437102; doi: https://doi.org/10.1101/2021.03.25.437102
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    Differential effects of loss of park7 activity on Iron Responsive Element (IRE) gene sets: Implications for the role of iron dyshomeostasis in the pathophysiology of Parkinson’s disease
    Hui Yung Chin, Michael Lardelli, Lyndsey Collins-Praino, Karissa Barthelson
    bioRxiv 2021.03.25.437102; doi: https://doi.org/10.1101/2021.03.25.437102

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