Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease

• Autor(a) principal: Castro, Andreia Cristiana Teixeira
• Data de Publicação: 2015
• Outros Autores: 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.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/1822/46243
• topic: Spinocerebellar ataxia type 3; Ataxin 3 aggregation; Therapy; Selective serotonin reuptake inhibitor; Citalopram; selective serotonin reuptake inhibitor, citalopram; Science & Technology

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.