A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons

eLife

Marina Sirota¹  Hao Li²  Jiashun Zheng²  Xiang Zhao³  James Shortland³  Daryl Nucum³  Longping Peng⁴  Su Guo⁵  Gha-Hyun J Kim⁵  Han Mo⁶  Bingwei Lu⁷  Zhihao Wu⁷  Benjamin Tang⁸  Harrison Liu⁹  Bo Huang^1,10  Adam R Renslo^1,11  Steven Chen^1,11  Michelle R Arkin^1,11  Mannuel Elepano^1,12  Nick Paras^1,12  Steven Olson^1,13 

[1] Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, United States;Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States;Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States;Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States;Department of Cardiovascular Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China;Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States;Graduate Program of Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, United States;Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States;Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Tsinghua University, Beijing, China;Department of Pathology, Stanford University School of Medicine, Stanford, United States;Department of Pathology, Stanford University School of Medicine, Stanford, United States;Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute forNeurosciences, University of California, San Francisco, San Francisco, United States;Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States;Graduate Program of Bioengineering, University of California, San Francisco, San Francisco, United States;Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States;Graduate Program of Bioengineering, University of California, San Francisco, San Francisco, United States;Chan Zuckerberg Biohub, San Francisco, United States;Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States;Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United States;Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute forNeurosciences, University of California, San Francisco, San Francisco, United States;Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United States;Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute forNeurosciences, University of California, San Francisco, San Francisco, United States;

关键词: phenotypic screening;    glucocerebrosidase (GBA);    parkin, pink1, a-synuclein, dj-1;    nitroreductase (NTR)-metronidazole (MTZ);    time to Levodopa (L-dopa);    electronic health records (EHR);    D. melanogaster;    Human;    Zebrafish;   

DOI  :  10.7554/eLife.69795

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY