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

Drosophila Proteins/deficiency
Drosophila Proteins/genetics
Databases, Factual
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism
Angiotensin-Converting Enzyme Inhibitors/therapeutic use
Case-Control Studies
Animals
Antiparkinson Agents/pharmacology*
Antiparkinson Agents/therapeutic use
Drosophila melanogaster/drug effects
Drosophila melanogaster/genetics
Drosophila melanogaster/metabolism
Neuroprotective Agents/pharmacology*
Neuroprotective Agents/therapeutic use
Parkinson Disease/drug therapy*
Parkinson Disease/genetics
Parkinson Disease/metabolism
Disease Models, Animal
Gaucher Disease/drug therapy
Gaucher Disease/genetics
Gaucher Disease/metabolism
Dopaminergic Neurons/drug effects*
Dopaminergic Neurons/metabolism
Mitochondria/drug effects*
Mitochondria/genetics
Mitochondria/metabolism
Renin-Angiotensin System/drug effects*
Renin-Angiotensin System/genetics
Zebrafish/genetics
Zebrafish/metabolism
Angiotensin II Type 1 Receptor Blockers/pharmacology*
Angiotensin II Type 1 Receptor Blockers/therapeutic use
Humans
Receptor, Angiotensin, Type 1/genetics
Receptor, Angiotensin, Type 1/metabolism
Animals, Genetically Modified
High-Throughput Screening Assays

(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