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Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease
- Title
- Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease
- Authors
- Teixeira-Castro, Andreia; Jalles, Ana; Esteves, Sofia; Kang, Soosung; Santos, Liliana da Silva; Silva-Fernandes, Anabela; Neto, Mario F.; Brielmann, Renee M.; Bessa, Carlos; Duarte-Silva, Sara; Miranda, Adriana; Oliveira, Stephanie; Neves-Carvalho, Andreia; Bessa, Joao; Summavielle, Teresa; Silverman, Richard B.; Oliveira, Pedro; Morimoto, Richard I.; Maciel, Patricia
- Ewha Authors
- 강수성
- SCOPUS Author ID
- 강수성
- Issue Date
- 2015
- Journal Title
- BRAIN
- ISSN
- 0006-8950
1460-2156
- Citation
- BRAIN vol. 138
- Keywords
- spinocerebellar ataxia type 3; ataxin 3 aggregation; therapy; selective serotonin reuptake inhibitor; citalopram
- Publisher
- OXFORD UNIV PRESS
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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.
- DOI
- 10.1093/brain/awv262
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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