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BrainVolume 138, Issue 11, November 2015, Pages 3221-3237

Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease(Article)(Open Access)

  • Teixeira-Castro, A.,
  • Jalles, A.,
  • Esteves, S.,
  • Kang, S.,
  • Da Silva Santos, L.,
  • Silva-Fernandes, A.,
  • Neto, M.F.,
  • Brielmann, R.M.,
  • Bessa, C.,
  • Duarte-Silva, S.,
  • Miranda, A.,
  • Oliveira, S.,
  • Neves-Carvalho, A.,
  • Bessa, J.,
  • Summavielle, T.,
  • Silverman, R.B.,
  • Oliveira, P.,
  • Morimoto, R.I.,
  • Maciel, P.
  • View Correspondence (jump link)
  • aLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4710-057, Portugal
  • bICVS/3Bs - PT Government Assoct. Laboratory, Braga/Guimarães, Portugal
  • cDepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208, United States
  • dRice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, United States
  • eDepartment of Chemistry, Northwestern University, Evanston, IL 60208, United States
  • fChemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, United States
  • gIBMC, Instituto de Biologia Molecular e Celular, Universidade Do Porto, Rua do Campo Alegre, 823, Porto, 4150-180, Portugal
  • hICBAS-Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal

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. © 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]

Author keywords

ataxin 3 aggregationselective serotonin reuptake inhibitor, citalopramspinocerebellar ataxia type 3therapy

Indexed keywords

EMTREE drug terms:ataxin 3budesonidechlortetracyclinecitalopramclemizoleestronemetixenenisoxetinenoscapineserotonin 1 receptorserotonin 4 receptorserotonin transportertiapridevinburnineataxin 3atx-3 protein, C elegansAtxn3 protein, mouseCaenorhabditis elegans proteincitaloprammod-5 protein, C elegansserotoninserotonin transporterserotonin uptake inhibitor
EMTREE medical terms:animal experimentanimal tissueArticleastrocytosisbody weightCaenorhabditis eleganscontrolled studydrug screeningMachado Joseph diseasemalemotor coordinationmotor performancemouseneurotoxicitynonhumanpathogenesispriority journalserotoninergic transmissionsignal transductionanimalanimal behaviorcell inclusiondisease modeldrug effectsgliosislocomotionMachado Joseph diseasemetabolismnerve cellpathologysynaptic transmissiontransgenic mouse
MeSH:AnimalsAtaxin-3Behavior, AnimalCaenorhabditis elegansCaenorhabditis elegans ProteinsCitalopramDisease Models, AnimalGliosisInclusion BodiesLocomotionMachado-Joseph DiseaseMiceMice, TransgenicNeuronsSerotoninSerotonin Plasma Membrane Transport ProteinsSerotonin Uptake InhibitorsSynaptic Transmission

Chemicals and CAS Registry Numbers:

budesonide, 51333-22-3, 51372-29-3; chlortetracycline, 12691-62-2, 57-62-5, 64-72-2, 78794-02-2; citalopram, 59729-33-8; clemizole, 1163-36-6, 442-52-4; estrone, 53-16-7; metixene, 1553-34-0, 4969-02-2, 7081-40-5; nisoxetine, 53179-07-0, 57754-86-6; noscapine, 128-62-1; tiapride, 51012-32-9, 51012-33-0; vinburnine, 474-00-0, 4880-88-0; serotonin, 50-67-9;

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

Manufacturers:

Drug manufacturer:

Kemprotec;

Lundbeck, Denmark;

Sigma

  • ISSN: 00068950
  • CODEN: BRAIA
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1093/brain/awv262
  • PubMed ID: 26373603
  • Document Type: Article
  • Publisher: Oxford University Press

  Maciel, P.; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal;
© Copyright 2015 Elsevier B.V., All rights reserved.

Cited by 26 documents

Klockgether, T. , Mariotti, C. , Paulson, H.L.
Spinocerebellar ataxia
(2019) Nature Reviews Disease Primers
Yang, Z.-H. , Shi, C.-H. , Zhou, L.-N.
Metabolic profiling reveals biochemical pathways and potential biomarkers of spinocerebellar ataxia 3
(2019) Frontiers in Molecular Neuroscience
Esteves, S. , Oliveira, S. , Duarte-Silva, S.
Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease
(2019) Molecular Neurobiology
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