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.

Nigral Neurons Degenerating in Parkinson's Disease Express the Angiotensin Receptor Type 1 Gene

“…Furthermore, an intracellular RAS was identified in mitochondria and nuclei of dopaminergic neurons, including other RAS components such as AGTR2 and MAS receptors that may counteract the deleterious effects of AGTR1 activation 4 . Recent clinical studies also support a neuroprotective effect of AGTR1 inhibitors 3,5 . The findings of Kamath et al 1 further encourage the development of prodromal clinical trials for angiotensin receptor blockers (ARBS) that can cross the blood‐brain barrier or for molecules inhibiting AGTR1 effects, including those acting on RAS regulatory components (AGTR2, MAS) that counteract AGTR1 activation.…”

In-vivo fast non-linear microscopy reveals impairment of fast axonal transport induced by molecular motor imbalances in the brain of zebrafish larvae

“…Finally, our assay could also be valuable to develop biomedical models reproducing human nervous system alterations quantitatively assess the link between axonal transport impairment and disease outcome. In particular, it would be interesting to reproduce our experiments in Zf larvae infected by neurotropic viruses, [47][48][49] in transgenic lines used as models of neurodegenerative diseases, [50][51][52] or upon axonal photoablation 53 to precisely measure the axonal transport impairments in these situations. In case of detection of a significant impairment of axonal transport, our assay could be harnessed to screen therapeutic compounds able to rescue the defect.…”

In Vivo Dopamine Neuron Imaging-Based Small Molecule Screen Identifies Novel Neuroprotective Compounds and Targets

“…Previously, we developed a high throughput DA neuron imaging method (Liu et al, 2016) and reported the identification of renin-angiotensin-aldosterone system (RAAS) inhibition as neuroprotective via mitochondrial targeting in DA neurons (Kim et al, 2021). In this study, we present for the first time the results of the entire 1403 HTS bioactive compound screen and uncover additional neuroprotective candidates after secondary validation.…”

“…While current therapeutic drug discovery is largely targetbased, the implementation of phenotypic drug discovery has significant advantages particularly for neurodegenerative diseases (Ibhazehiebo et al, 2018;Lam and Peterson, 2019;Kim et al, 2021;Zhang et al, 2021). Phenotypic assays for a direct impact on neuronal integrity can bypass the need to fully understand complex biological processes underlying neurodegeneration, and in many cases provide leads to novel targets (Liu et al, 2016;Moffat et al, 2017).…”

“…Neither genetic models nor neurotoxin (e.g., MPTP) models of PD offer such strength, due to late onset, weak or variable DA neuronal loss. The NTR converts MTZ to the toxic nitroso radical form (Curado et al, 2008;Pisharath and Parsons, 2009;Williams et al, 2015) in vivo causing DA neuronal loss that is quantifiable in the ventral forebrain region and involves mitochondrial dysfunction (Kim et al, 2021).…”