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

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 s...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	phenotypic screening glucocerebrosidase (GBA) parkin, pink1, a-synuclein, dj-1 nitroreductase (NTR)-metronidazole (MTZ) time to Levodopa (L-dopa) electronic health records (EHR) Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1a2b18fbbd014e52b754a5691eee90b7
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spelling	oai:doaj.org-article:1a2b18fbbd014e52b754a5691eee90b72021-11-30T10:05:57ZA zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons10.7554/eLife.697952050-084Xe69795https://doaj.org/article/1a2b18fbbd014e52b754a5691eee90b72021-09-01T00:00:00Zhttps://elifesciences.org/articles/69795https://doaj.org/toc/2050-084XParkinson’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.Gha-Hyun J KimHan MoHarrison LiuZhihao WuSteven ChenJiashun ZhengXiang ZhaoDaryl NucumJames ShortlandLongping PengMannuel ElepanoBenjamin TangSteven OlsonNick ParasHao LiAdam R RensloMichelle R ArkinBo HuangBingwei LuMarina SirotaSu GuoeLife Sciences Publications Ltdarticlephenotypic screeningglucocerebrosidase (GBA)parkin, pink1, a-synuclein, dj-1nitroreductase (NTR)-metronidazole (MTZ)time to Levodopa (L-dopa)electronic health records (EHR)MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	phenotypic screening glucocerebrosidase (GBA) parkin, pink1, a-synuclein, dj-1 nitroreductase (NTR)-metronidazole (MTZ) time to Levodopa (L-dopa) electronic health records (EHR) Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	phenotypic screening glucocerebrosidase (GBA) parkin, pink1, a-synuclein, dj-1 nitroreductase (NTR)-metronidazole (MTZ) time to Levodopa (L-dopa) electronic health records (EHR) Medicine R Science Q Biology (General) QH301-705.5 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 A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
description	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.
format	article
author	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
author_facet	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
author_sort	Gha-Hyun J Kim
title	A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
title_short	A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
title_full	A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
title_fullStr	A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
title_full_unstemmed	A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
title_sort	zebrafish screen reveals renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/1a2b18fbbd014e52b754a5691eee90b7
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A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons

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