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

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.

• Authors: 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
• Journal: Brain : a journal of neurology (Brain) Vol. 138 Issue Pt 11 Pg. 3221-37 (Nov 2015) ISSN: 1460-2156 [Electronic] England
• PMID: 26373603 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Caenorhabditis elegans Proteins
• Serotonin Plasma Membrane Transport Proteins
• Serotonin Uptake Inhibitors
• mod-5 protein, C elegans
• Citalopram
• Serotonin
• Ataxin-3
• Atxn3 protein, mouse
• atx-3 protein, C elegans

Topics

• Animals
• Ataxin-3 (drug effects, metabolism)
• Behavior, Animal (drug effects)
• Caenorhabditis elegans
• Caenorhabditis elegans Proteins (drug effects, metabolism)
• Citalopram (pharmacology)
• Disease Models, Animal
• Gliosis (metabolism)
• Inclusion Bodies (drug effects, metabolism, pathology)
• Locomotion (drug effects)
• Machado-Joseph Disease (metabolism)
• Mice
• Mice, Transgenic
• Neurons (drug effects, metabolism, pathology)
• Serotonin (metabolism)
• Serotonin Plasma Membrane Transport Proteins
• Selective Serotonin Reuptake Inhibitors (pharmacology)
• Synaptic Transmission (drug effects)