Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. Knockdown of the angiotensin receptor 1 ( agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. 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. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. Parkinson’s disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Bakar Computational Health Sciences Institute, University of California, San Francisco, United States.Chan Zuckerberg Biohub, United States.Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute forNeurosciences, University of California, San Francisco, United States.Department of Cardiovascular Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, China.Department of Biochemistry and Biophysics, University of California, San Francisco, United States.Small Molecule Discovery Center, University of California, San Francisco, United States.Department of Pathology, Stanford University School of Medicine, United States.Graduate Program of Bioengineering, University of California, San Francisco, United States.Department of Pharmaceutical Chemistry, University of California, San Francisco, United States.Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Tsinghua University, China.Graduate Program of Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, United States.
Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, United States.