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.
Date: 2015
Persistent ID: https://hdl.handle.net/1822/46243
Origin: RepositóriUM - Universidade do Minho
Subject(s): Spinocerebellar ataxia type 3; Ataxin 3 aggregation; Therapy; Selective serotonin reuptake inhibitor; Citalopram; selective serotonin reuptake inhibitor, citalopram
Description
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.
