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

Autor: Sofia Esteves, Pedro Oliveira, Renée M. Brielmann, Mário F. Neto, Andreia Teixeira-Castro, Carlos Bessa, Stéphanie Oliveira, Soosung Kang, Anabela Silva-Fernandes, Liliana Santos, Andreia Neves-Carvalho, João Bessa, Richard I. Morimoto, Patrícia Maciel, Sara Duarte-Silva, Adriana Miranda, Richard B. Silverman, Teresa Summavielle, Ana Jalles
Přispěvatelé: [et al.], Universidade do Minho
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Neurotoxicity Syndrome
congenital
hereditary
and neonatal diseases and abnormalities
Serotonin
Serotonin reuptake inhibitor
Mice
Transgenic
Citalopram
Pharmacology
Serotonergic
Synaptic Transmission
Mice
Spinocerebellar ataxia type 3
Ataxin 3 aggregation
medicine
Animals
Gliosis
Ataxin-3
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Serotonin transporter
Inclusion Bodies
Neurons
Serotonin Plasma Membrane Transport Proteins
Science & Technology
biology
Behavior
Animal
Neurotoxicity
Original Articles
Machado-Joseph Disease
selective serotonin reuptake inhibitor
citalopram
medicine.disease
Selective serotonin reuptake inhibitor
3. Good health
Disease Models
Animal
Ataxin
biology.protein
Therapy
Neurology (clinical)
Machado–Joseph disease
Neuroscience
Locomotion
Selective Serotonin Reuptake Inhibitors
medicine.drug
Zdroj: Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
Popis: 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.
This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through the projects ‘[PTDC/SAU-GMG/112617/2009] (to P.M.) and [EXPL/ BIM-MEC/0239/2012] (to A.T.C.)’, by National Ataxia foundation (to P.M.), by Ataxia UK (to P.M.), by National Institutes of Health (NIH) ‘[GM038109, GM081192, AG026647, and NS047331] (to R.I.M.)’, by The Chicago Biomedical Consortium (to R.I.M.) and by the Ellison Medical Foundation (to R.I.M.). A.T.C., A.J., S.E., L.S.S., C.B., S.D.S., A.S.F. and A.N.C. were supported by the FCT individual fellowships SFRH/BPD/79469/2011, SFRH/BD/76613/2011, SFRH/BD/78554/2011, SFRH/BD/ 84650/2012, SFRH/BPD/74452/2010, SFRH/BD/78388/ 2011, SFRH/BPD/91562/2012 and SFRH/BD/51059/2010, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa and EU/FSE.
info:eu-repo/semantics/publishedVersion
Databáze: OpenAIRE
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