Cargando…
A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment
Dopamine replacement represents the standard therapy for Parkinson’s disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molec...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804136/ https://www.ncbi.nlm.nih.gov/pubmed/34697772 http://dx.doi.org/10.1007/s13311-021-01134-2 |
_version_ | 1784643009190559744 |
---|---|
author | Sanz, Francisco José Solana-Manrique, Cristina Torres, Josema Masiá, Esther Vicent, María J. Paricio, Nuria |
author_facet | Sanz, Francisco José Solana-Manrique, Cristina Torres, Josema Masiá, Esther Vicent, María J. Paricio, Nuria |
author_sort | Sanz, Francisco José |
collection | PubMed |
description | Dopamine replacement represents the standard therapy for Parkinson’s disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood–brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01134-2. |
format | Online Article Text |
id | pubmed-8804136 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-88041362022-02-02 A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment Sanz, Francisco José Solana-Manrique, Cristina Torres, Josema Masiá, Esther Vicent, María J. Paricio, Nuria Neurotherapeutics Original Article Dopamine replacement represents the standard therapy for Parkinson’s disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood–brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01134-2. Springer International Publishing 2021-10-25 2021-10 /pmc/articles/PMC8804136/ /pubmed/34697772 http://dx.doi.org/10.1007/s13311-021-01134-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Sanz, Francisco José Solana-Manrique, Cristina Torres, Josema Masiá, Esther Vicent, María J. Paricio, Nuria A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment |
title | A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment |
title_full | A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment |
title_fullStr | A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment |
title_full_unstemmed | A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment |
title_short | A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson’s Disease Treatment |
title_sort | high-throughput chemical screen in dj-1β mutant flies identifies zaprinast as a potential parkinson’s disease treatment |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804136/ https://www.ncbi.nlm.nih.gov/pubmed/34697772 http://dx.doi.org/10.1007/s13311-021-01134-2 |
work_keys_str_mv | AT sanzfranciscojose ahighthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT solanamanriquecristina ahighthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT torresjosema ahighthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT masiaesther ahighthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT vicentmariaj ahighthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT paricionuria ahighthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT sanzfranciscojose highthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT solanamanriquecristina highthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT torresjosema highthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT masiaesther highthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT vicentmariaj highthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment AT paricionuria highthroughputchemicalscreenindj1bmutantfliesidentifieszaprinastasapotentialparkinsonsdiseasetreatment |