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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 (\n                    <jats:italic>agtr1<\/jats:italic>\n                    ) 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\n                    <jats:italic>Drosophila pink1<\/jats:italic>\n                    -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.\n                  <\/jats:p>","DOI":"10.7554\/elife.69795","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T11:01:34Z","timestamp":1632308494000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.69795","source":"Crossref","is-referenced-by-count":51,"title":["A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9073-2034","authenticated-orcid":true,"given":"Gha-Hyun J","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco","place":["San 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