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Molecular Neurobiology

, Volume 56, Issue 12, pp 8306–8322 | Cite as

Dysregulation in the Brain Protein Profile of Zebrafish Lacking the Parkinson’s Disease-Related Protein DJ-1

  • Amanda J. Edson
  • Helena A. Hushagen
  • Ann Kristin Frøyset
  • Inga Elda
  • Essa A. Khan
  • Antonio Di Stefano
  • Kari E. FladmarkEmail author
Article

Abstract

DJ-1 is a protein with a wide range of functions importantly related to redox regulation in the cell. In humans, dysfunction of the PARK7 gene is associated with neurodegeneration and Parkinson’s disease. Our objective was to establish a novel DJ-1 knockout zebrafish line and to identify early brain proteome changes, which could be linked to later pathology. The CRISPR-Cas9 method was used to target exon 1 of the park7-/- gene to produce a transgenic DJ-1-deficient zebrafish model of Parkinson’s disease. Label-free mass spectrometry was employed to identify altered protein expression in the DJ-1 null brain of early adult animals. The park7−/− line appears to develop normally at young adult and larval stages. With aging however, DJ-1 null fish exhibit lower tyrosine hydroxylase levels, respiratory failure in skeletal muscle, and lower body mass which is especially prevalent among male fish. By proteomic analysis of early adult brains, we determined that less than 5% of the 4091 identified proteins were influenced by the lack of DJ-1. The dysregulated proteins were mainly proteins known to be involved in mitochondrial metabolism, mitophagy, stress response, redox regulation, and inflammation. This dysregulation in protein networks of our novel DJ-1-deficient zebrafish model occurs in the early adult stage preceding a Parkinson’s disease-related phenotype and the reduction of tyrosine hydroxylase level. The identified protein changes provide new mechanistic background for DJ-1 function. The experimental power of zebrafish makes this model a highly valuable tool to understand and modulate cellular signaling leading to neurodegeneration.

Keywords

DJ-1 park7 Parkinson’s disease Zebrafish Proteomics CRISPR 

Abbreviations

CRISPR-Cas9

Clustered regularly spaced palindromic repeat-associated protein 9

PAM

Protospacer adjacent motif

gRNA

Guide RNA

dpf

Days post-fertilization

KO

Knockout (park7−/−)

bp

Base pair

WT

Tübingen AB wild type

DA

Dopamine

gst

Glutathione S-transferase

abce1

ATP-binding cassette, subfamily E, member 1

th

Tyrosine hydroxylase

gfap

Glial fibrillary acidic protein

GPX

Glutathione peroxidases

Nrf2

Nuclear factor (erythroid-derived 2)-like 2

ERK1/2

Extracellular signal-regulated kinase

asl

Argininosuccinate lysate

C3

Complement complex 3

CTDSP1

C-terminal domain small phosphatase 1

Notes

Acknowledgments

We wish to thank Puja Thiel for performing the zebrafish injections and Mikkel Espolin Birkeland for dissection of zebrafish. Mass spectrometry analysis was carried out at the Proteomics Core Facility at the University of Bergen (PROBE). The CRISPR-Cas9 plasmids were received from the Suster Lab at Uni Research AS. The authors also wish to thank Sushma Grellscheid and Thomas Stevenson for discussions regarding stress granules.

Author Contributions

AJE and KEF designed the study and wrote the paper. AJE, AKF, HAH, IE, and EAK performed the experiments. ADS performed the dopamine analysis. AJE, KEF, and AKF analyzed the data.

Funding

This research was funded by grants from Advokat Rolf Sandberg Rebergs and Ellen Marie Rebergs legat (KEF), Det alminnelige naturvitenskapelige forskningsfond, UiB (AJE), and COST action 16112 (KEF and ADS).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Bergen where the studies were conducted. Establishment of the park7−/− (KO) line and euthanization of adult fish were approved by the Norwegian National Animal Research Authority at Mattilsynet (FOTS ID8039 and ID14039).

Supplementary material

12035_2019_1667_MOESM1_ESM.xlsx (666 kb)
Online resource 1 Proteins identified by mass spectrometry from park7−/− and wild-type 3-month-old zebrafish brains. Proteins identified by site or reverse were removed in addition to removal of potential contaminants. Proteins with a score less than 4 and those identified by only a single unique peptide were also removed. In order to determine the fold change, a two-sample Student’s t test was run (S0 = 2; p value threshold = 0.05) on proteins with at least 3 valid values in both KO and WT samples. Those proteins that did not meet the criteria for the t test have a fold change and p value not determined (n.d.). LFQ intensities are present after log2 transformation, and invalid values are shown as NaN. KO, park7−/−; WT, wild type. (XLSX 665 kb)
12035_2019_1667_MOESM2_ESM.xlsx (7.3 mb)
Online resource 2 All peptides identified by mass spectrometry from park7−/− (KO) and wild-type (WT) adult zebrafish brains. LFQ intensities are presented after log2 transformation. (XLSX 7513 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of BergenBergenNorway
  2. 2.Department of PharmacyUniversity of “G. D’Annunzio”ChietiItaly

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