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https://hdl.handle.net/1822/46243
Título: | Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease |
Autor(es): | 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. |
Palavras-chave: | Spinocerebellar ataxia type 3 Ataxin 3 aggregation Therapy Selective serotonin reuptake inhibitor Citalopram selective serotonin reuptake inhibitor, citalopram |
Data: | 2015 |
Editora: | Oxford University Press |
Revista: | Brain |
Resumo(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. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/46243 |
DOI: | 10.1093/brain/awv262 |
ISSN: | 0006-8950 |
e-ISSN: | 1460-2156 |
Versão da editora: | http://brain.oxfordjournals.org/ |
Arbitragem científica: | yes |
Acesso: | Acesso aberto |
Aparece nas coleções: | ICVS - Artigos em revistas internacionais / Papers in international journals |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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teixeira-castro a et al 2015_serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of machado-joseph disease.pdf | 3,25 MB | Adobe PDF | Ver/Abrir |