Loss of park7 activity has differential effects on expression of iron responsive element (IRE) gene sets in the brain transcriptome in a zebrafish model of Parkinson’s disease

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.

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology

“…Mitochondrial membrane potential is also reduced in DJ-1 knockout mouse embryonic fibroblasts [34]. Analysis of transcriptome data from park7−/− zebrafish brains suggests that mitochondrial oxidative stress and iron dyshomeostasis comprise early preclinical events in PD [36].…”

The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes

“…Park7 is expressed ubiquitously and was originally identified in dopaminergic neurons of familial Parkinson's disease patients. [18] Chin et al observed altered IRE gene transcript abundance in Park7 knockout zebrafish brain [43] and Lin et al reported a novel PARK7 homozygous mutation (c.390delA) responsible for autosomal recessive early-onset Parkinson Disease. [44] Loss of myocardial Park7 protein has been observed in end-stage heart failure patients [19] and Park7 knockout mice were more vulnerable to myocardial infarction and pressure overload challenges.…”

Zebrafish, Medaka and Turquoise Killifish for Understanding Human Neurodegenerative/Neurodevelopmental Disorders

“…In the case of zebrafish, single depletion of Pink1 is sufficient to induce the loss of dopaminergic neurons [99][100][101]. DJ-1 knockout zebrafish and medaka models have also been created, which need further pathological evaluations but are promising for the production of new fish models of Parkinson's disease [102][103][104][105].…”