PUBLICATION

A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons

Authors
Kim, G.J., Mo, H., Liu, H., Wu, Z., Chen, S., Zheng, J., Zhao, X., Nucum, D., Shortland, J., Peng, L., Elepano, M., Tang, B., Olson, S., Paras, N., Li, H., Renslo, A.R., Arkin, M.R., Huang, B., Lu, B., Sirota, M., Guo, S.
ID
ZDB-PUB-210923-11
Date
2021
Source
eLIFE   10: (Journal)
Registered Authors
Guo, Su
Keywords
D. melanogaster, electronic health records (EHR), genetics, genomics, glucocerebrosidase (GBA), human, neuroscience, nitroreductase (NTR)-metronidazole (MTZ), parkin, pink1, a-synuclein, dj-1, phenotypic screening, time to Levodopa (L-dopa), zebrafish
MeSH Terms
  • Antiparkinson Agents/pharmacology*
  • Antiparkinson Agents/therapeutic use
  • Databases, Factual
  • Angiotensin II Type 1 Receptor Blockers/pharmacology*
  • Angiotensin II Type 1 Receptor Blockers/therapeutic use
  • Neuroprotective Agents/pharmacology*
  • Neuroprotective Agents/therapeutic use
  • Mitochondria/drug effects*
  • Mitochondria/genetics
  • Mitochondria/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Receptor, Angiotensin, Type 1/genetics
  • Receptor, Angiotensin, Type 1/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drosophila melanogaster/drug effects
  • Drosophila melanogaster/genetics
  • Drosophila melanogaster/metabolism
  • Gaucher Disease/drug therapy
  • Gaucher Disease/genetics
  • Gaucher Disease/metabolism
  • Angiotensin-Converting Enzyme Inhibitors/therapeutic use
  • Parkinson Disease/drug therapy*
  • Parkinson Disease/genetics
  • Parkinson Disease/metabolism
  • Animals
  • Humans
  • Case-Control Studies
  • Drosophila Proteins/deficiency
  • Drosophila Proteins/genetics
  • Dopaminergic Neurons/drug effects*
  • Dopaminergic Neurons/metabolism
  • High-Throughput Screening Assays
  • Renin-Angiotensin System/drug effects*
  • Renin-Angiotensin System/genetics
(all 38)
PubMed
34550070 Full text @ Elife
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.
Genes / Markers
Figures
Figure Gallery (7 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ABchemical treatment by environment: conduritol B epoxide, chemical treatment by environment: L-dopaDay 5
ABchemical treatment by environment: conduritol B epoxide, chemical treatment by environment: L-dopaDay 5
ABchemical treatment by environment: L-dopa, chemical treatment by environment: olmesartanDay 5
ABchemical treatment by environment: L-dopa, chemical treatment by environment: olmesartanDay 5
ABchemical treatment by environment: conduritol B epoxideDay 5
ABchemical treatment by environment: conduritol B epoxideDay 5
ABchemical treatment by environment: L-dopaDay 5
ABchemical treatment by environment: olmesartanDay 5
c264Tg/c264Tg; s2509Tg/s2509Tgstandard conditionsDay 5
c264Tg/c264Tg; s2509Tg/s2509Tgstandard conditionsDay 6
1 - 10 of 56
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    ion32TgTransgenic Insertion
    pt420TgTransgenic Insertion
      s2509TgTransgenic Insertion
        1 - 4 of 4
        Show
        Human Disease / Model
        Human Disease Fish Conditions Evidence
        Gaucher's diseasethion32Tg/ion32Tg; c264Tg/c264Tgchemical treatment by environment: conduritol B epoxideTAS
        Parkinson's diseasethion32Tg/ion32Tg; c264Tg/c264Tgchemical treatment by environment: metronidazoleTAS
        Parkinson's diseasethion32Tg/ion32Tg; c264Tg/c264Tgchemical treatment by environment: conduritol B epoxideTAS
        1 - 3 of 3
        Show
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        agtr1aCRISPR1-agtr1aCRISPR
        agtr1aCRISPR2-agtr1bCRISPR
        agtr1aMO1-agtr1aMRPHLNO
        agtr1bCRISPR1-agtr1aCRISPR
        agtr1bCRISPR2-agtr1bCRISPR
        agtr1bMO1-agtr1bMRPHLNO
        1 - 6 of 6
        Show
        Fish
        Fish
        AB
        c264Tg/c264Tg; s2509Tg/s2509Tg
        s2509Tg/s2509Tg
        s2509Tg/s2509Tg + MO1-agtr1a + MO1-agtr1b
        thion32Tg/ion32Tg; c264Tg/c264Tg
        thion32Tg/ion32Tg; c264Tg/c264Tg + CRISPR1-agtr1a + CRISPR2-agtr1b
        thion32Tg/ion32Tg; pt420Tg/pt420Tg
        1 - 7 of 7
        Show
        Antibodies
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        DsRed2EFGDsRed2
        EGFPEFGEGFP
        GAL4EFGGAL4
        GFPEFGGFP
        mCherryEFGmCherry
        NTREFGNTR
        1 - 6 of 6
        Show
        Mapping
        No data available
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        Citation
        Kim, G.J., Mo, H., Liu, H., Wu, Z., Chen, S., Zheng, J., Zhao, X., Nucum, D., Shortland, J., Peng, L., Elepano, M., Tang, B., Olson, S., Paras, N., Li, H., Renslo, A.R., Arkin, M.R., Huang, B., Lu, B., Sirota, M., Guo, S. (2021) A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons. eLIFE. 10:.