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
-
- Animals
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Renin-Angiotensin System/drug effects*
- Renin-Angiotensin System/genetics
- High-Throughput Screening Assays
- Disease Models, Animal
- Dopaminergic Neurons/drug effects*
- Dopaminergic Neurons/metabolism
- Parkinson Disease/drug therapy*
- Parkinson Disease/genetics
- Parkinson Disease/metabolism
- Case-Control Studies
- Zebrafish/genetics
- Zebrafish/metabolism
- Animals, Genetically Modified
- Antiparkinson Agents/pharmacology*
- Antiparkinson Agents/therapeutic use
- Angiotensin-Converting Enzyme Inhibitors/therapeutic use
- Drosophila melanogaster/drug effects
- Drosophila melanogaster/genetics
- Drosophila melanogaster/metabolism
- Angiotensin II Type 1 Receptor Blockers/pharmacology*
- Angiotensin II Type 1 Receptor Blockers/therapeutic use
- Gaucher Disease/drug therapy
- Gaucher Disease/genetics
- Gaucher Disease/metabolism
- Drosophila Proteins/deficiency
- Drosophila Proteins/genetics
- Databases, Factual
- Mitochondria/drug effects*
- Mitochondria/genetics
- Mitochondria/metabolism
- Neuroprotective Agents/pharmacology*
- Neuroprotective Agents/therapeutic use
- Humans
- PubMed
- 34550070 Full text @ Elife
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:.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping