Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease.
Brain
; 138(Pt 11): 3221-37, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26373603
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Citalopram
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Serotonina
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Cuerpos de Inclusión
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Inhibidores Selectivos de la Recaptación de Serotonina
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Enfermedad de Machado-Joseph
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Proteínas de Caenorhabditis elegans
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Ataxina-3
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Gliosis
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Locomoción
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Neuronas
Límite:
Animals
Idioma:
En
Revista:
Brain
Año:
2015
Tipo del documento:
Article