{"doi":"10.7554/elife.69795","title":"A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons","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.","journal":"eLife","year":2021,"id":157739,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":49,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":665709,"name":"Han Mo","orcid":null,"position":1,"is_corresponding":false},{"id":665125,"name":"Harrison Liu","orcid":"0000-0001-8441-6908","position":2,"is_corresponding":false},{"id":354151,"name":"Zhihao Wu","orcid":"0000-0003-3080-5769","position":3,"is_corresponding":false},{"id":371533,"name":"Steven Chen","orcid":"0000-0003-3239-4975","position":4,"is_corresponding":false},{"id":665126,"name":"Jiashun Zheng","orcid":"0000-0003-3266-4461","position":5,"is_corresponding":false},{"id":564552,"name":"Xiang Zhao","orcid":"0000-0002-3339-4806","position":6,"is_corresponding":false},{"id":665127,"name":"Daryl Nucum","orcid":"0000-0001-8242-2941","position":7,"is_corresponding":false},{"id":665710,"name":"James Shortland","orcid":null,"position":8,"is_corresponding":false},{"id":665128,"name":"Longping Peng","orcid":"0000-0003-2012-1814","position":9,"is_corresponding":false},{"id":665711,"name":"Mannuel Elepano","orcid":null,"position":10,"is_corresponding":false},{"id":440280,"name":"Benjamin C. Tang","orcid":"0000-0002-3807-0480","position":11,"is_corresponding":false},{"id":403981,"name":"Steven H. Olson","orcid":"0000-0001-9615-9355","position":12,"is_corresponding":false},{"id":5843,"name":"Nick A. Paras","orcid":"0000-0001-5742-4056","position":13,"is_corresponding":false},{"id":665129,"name":"Hao Li","orcid":"0000-0003-4889-953X","position":14,"is_corresponding":false},{"id":490827,"name":"Adam R. Renslo","orcid":"0000-0002-1240-2846","position":15,"is_corresponding":false},{"id":246284,"name":"Michelle R. Arkin","orcid":"0000-0002-9366-6770","position":16,"is_corresponding":false},{"id":406504,"name":"Bo Huang","orcid":"0000-0003-1704-4141","position":17,"is_corresponding":false},{"id":307374,"name":"Bingwei Lu","orcid":"0000-0002-5807-7014","position":18,"is_corresponding":false},{"id":2824,"name":"Marina Sirota","orcid":"0000-0002-7246-6083","position":19,"is_corresponding":false},{"id":307375,"name":"Su Guo","orcid":"0000-0002-7342-0108","position":20,"is_corresponding":false},{"id":665124,"name":"Ghahyun J. Kim","orcid":"0000-0001-9073-2034","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-18T23:44:21.786014Z","pmid":"34550070","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}