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

Brain : a journal of neurology (2015-09-17)
Andreia Teixeira-Castro, Ana Jalles, Sofia Esteves, Soosung Kang, Liliana da Silva Santos, Anabela Silva-Fernandes, Mário F Neto, Renée M Brielmann, Carlos Bessa, Sara Duarte-Silva, Adriana Miranda, Stéphanie Oliveira, Andreia Neves-Carvalho, João Bessa, Teresa Summavielle, Richard B Silverman, Pedro Oliveira, Richard I Morimoto, Patrícia Maciel
ABSTRACT

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.

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