NAGIOS: RODERIC FUNCIONANDO

A high-throughput chemical screen in DJ-1β mutant flies identifies zaprinast as a potential Parkinson's disease treatment

Repositori DSpace/Manakin

IMPORTANT: Aquest repositori està en una versió antiga des del 3/12/2023. La nova instal.lació está en https://roderic.uv.es/

A high-throughput chemical screen in DJ-1β mutant flies identifies zaprinast as a potential Parkinson's disease treatment

dc.contributor.author	Sanz, Francisco José
dc.contributor.author	Solana Manrique, Cristina
dc.contributor.author	Torres Ibáñez, José Manuel
dc.contributor.author	Masiá, Esther
dc.contributor.author	Vicent Docón, María Jesús
dc.contributor.author	Paricio Ortiz, Nuria
dc.date.accessioned	2022-10-21T14:37:26Z
dc.date.available	2022-10-21T14:37:26Z
dc.date.issued	2021
dc.identifier.citation	Sanz, Francisco José Solana Manrique, Cristina Torres Ibáñez, José Manuel Masiá, Esther Vicent Docón, María Jesús Paricio Ortiz, Nuria 2021 A high-throughput chemical screen in DJ-1β mutant flies identifies zaprinast as a potential Parkinson's disease treatment Neurotherapeutics 18 4 2565 2578
dc.identifier.uri	https://hdl.handle.net/10550/84240
dc.description.abstract	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.
dc.language.iso	eng
dc.relation.ispartof	Neurotherapeutics, 2021, vol. 18, num. 4, p. 2565-2578
dc.subject	Sistema nerviós central Malalties
dc.subject	Neurologia
dc.title	A high-throughput chemical screen in DJ-1β mutant flies identifies zaprinast as a potential Parkinson's disease treatment
dc.type	journal article	es_ES
dc.date.updated	2022-10-21T14:37:26Z
dc.identifier.doi	10.1007/s13311-021-01134-2
dc.identifier.idgrec	148188
dc.rights.accessRights	open access	es_ES