title: 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.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal 3 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA 4 Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Andreia
authors.initials: A
authors.lastname: Teixeira-Castro
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal pmaciel@ecsaude.uminho.pt.
authors.forename: Ana
authors.initials: A
authors.lastname: Jalles
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal pmaciel@ecsaude.uminho.pt.
authors.forename: Sofia
authors.initials: S
authors.lastname: Esteves
authors.affiliation: 3 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA 5 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA 6 Chemistry of Life Processes Institute and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Soosung
authors.initials: S
authors.lastname: Kang
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: da Silva Santos
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Silva-Fernandes
authors.affiliation: 3 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA 4 Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Mário F
authors.initials: MF
authors.lastname: Neto
authors.affiliation: 3 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA 4 Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Brielmann
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bessa
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Duarte-Silva
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Adriana
authors.initials: A
authors.lastname: Miranda
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Oliveira
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Neves-Carvalho
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Bessa
authors.affiliation: 7 IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Summavielle
authors.affiliation: 3 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA 5 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA 6 Chemistry of Life Processes Institute and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.affiliation: 8 ICBAS-Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Oliveira
authors.affiliation: 3 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA 4 Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal 2 ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal pmaciel@ecsaude.uminho.pt.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Maciel
mesh_terms: D000818:Animals; D000067699:Ataxin-3 / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology*; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism*; D002479:Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008124:Locomotion / Q000187:drug effects*; D017827:Machado-Joseph Disease / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000067699:Ataxin-3; D029742:Caenorhabditis elegans Proteins; D015283:Citalopram; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493229:mod-5 protein, C elegans; C511594:Atxn3 protein, mouse; C519526:atx-3 protein, C elegans
keywords: ataxin 3 aggregation; selective serotonin reuptake inhibitor, citalopram; spinocerebellar ataxia type 3; therapy