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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 22, 2021
- Source ID
- 10.7554/elife.69795
Entities
People
- Adam R Renslo
- Bingwei Lu
- Bo Huang
- Brian H. Tang
- Daryl Nucum
- Ghahyun J. Kim
- Han Mo
- Hao Li
- Harrison Liu
- James Shortland
- Jiashun Zheng
- Longping Peng
- Mannuel Elepano
- Marina Sirota
- Michelle R Arkin
- Nick Paras
- Steven Chen
- Steven Olson
- Su Guo
- Xiang Zhao
- Zhihao Wu
Organizations
- Chan Zuckerberg Initiative
- National Institutes of Health
- Shanghai University of Traditional Chinese Medicine
- Stanford University
- Tsinghua University
- United States Department of Defense
- University of California
- University of California, San Francisco