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TitleSerotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease
Author(s)Castro, Andreia Cristiana Teixeira
Sousa, Ana Luísa Jales Monteiro
Esteves, Sofia
Santos, Liliana da Silva
Fernandes, Anabela Silva
Bessa, Carlos Jorge Pereira
Silva, Sara Carina Duarte
Miranda, Adriana
Oliveira, Stéphanie Pereira
Carvalho, Andreia Alexandra Neves
Bessa, João
Maciel, P.
KeywordsSpinocerebellar ataxia type 3
Ataxin 3 aggregation
Selective serotonin reuptake inhibitor
selective serotonin reuptake inhibitor, citalopram
Issue date2015
PublisherOxford University Press
Abstract(s)Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease.
Publisher version
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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