eLife (Sep 2021)
A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
- Gha-Hyun J Kim,
- Han Mo,
- Harrison Liu,
- Zhihao Wu,
- Steven Chen,
- Jiashun Zheng,
- Xiang Zhao,
- Daryl Nucum,
- James Shortland,
- Longping Peng,
- Mannuel Elepano,
- Benjamin Tang,
- Steven Olson,
- Nick Paras,
- Hao Li,
- Adam R Renslo,
- Michelle R Arkin,
- Bo Huang,
- Bingwei Lu,
- Marina Sirota,
- Su Guo
Affiliations
- Gha-Hyun J Kim
- ORCiD
- 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
- Han Mo
- 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
- Harrison Liu
- 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
- Zhihao Wu
- Department of Pathology, Stanford University School of Medicine, Stanford, United States
- Steven Chen
- 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
- Jiashun Zheng
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
- Xiang Zhao
- Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States
- Daryl Nucum
- Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States
- James Shortland
- Department of Bioengineering and Therapeutic Sciences and Programs in BiologicalSciences and Human Genetics, University of California, San Francisco, San Francisco, United States
- Longping Peng
- 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
- Mannuel Elepano
- Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute forNeurosciences, University of California, San Francisco, San Francisco, United States
- Benjamin Tang
- 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
- Steven Olson
- 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
- Nick Paras
- Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute forNeurosciences, University of California, San Francisco, San Francisco, United States
- Hao Li
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
- Adam R Renslo
- 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
- Michelle R Arkin
- 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
- Bo Huang
- ORCiD
- 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
- Bingwei Lu
- Department of Pathology, Stanford University School of Medicine, Stanford, United States
- Marina Sirota
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, United States
- Su Guo
- ORCiD
- 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
- DOI
- https://doi.org/10.7554/eLife.69795
- Journal volume & issue
-
Vol. 10
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.
Keywords
- phenotypic screening
- glucocerebrosidase (GBA)
- parkin, pink1, a-synuclein, dj-1
- nitroreductase (NTR)-metronidazole (MTZ)
- time to Levodopa (L-dopa)
- electronic health records (EHR)
