TY - JOUR
T1 - Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease
AU - Teixeira-Castro, Andreia
AU - Jalles, Ana
AU - Esteves, Sofia
AU - Kang, Soosung
AU - Da Silva Santos, Liliana
AU - Silva-Fernandes, Anabela
AU - Neto, Mário F.
AU - Brielmann, Renée M.
AU - Bessa, Carlos
AU - Duarte-Silva, Sara
AU - Miranda, Adriana
AU - Oliveira, Stéphanie
AU - Neves-Carvalho, Andreia
AU - Bessa, João
AU - Summavielle, Teresa
AU - Silverman, Richard B.
AU - Oliveira, Pedro
AU - Morimoto, Richard I.
AU - Maciel, Patrícia
N1 - Publisher Copyright:
© 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
KW - ataxin 3 aggregation
KW - selective serotonin reuptake inhibitor, citalopram
KW - spinocerebellar ataxia type 3
KW - therapy
UR - https://www.scopus.com/pages/publications/84947806720
U2 - 10.1093/brain/awv262
DO - 10.1093/brain/awv262
M3 - Article
C2 - 26373603
AN - SCOPUS:84947806720
SN - 0006-8950
VL - 138
SP - 3221
EP - 3237
JO - Brain
JF - Brain
IS - 11
ER -