期刊
BRAIN
卷 138, 期 -, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awv262
关键词
spinocerebellar ataxia type 3; ataxin 3 aggregation; therapy; selective serotonin reuptake inhibitor; citalopram
资金
- Fundacao para a Ciencia e Tecnologia (FCT)
- COMPETE [PTDC/SAU-GMG/112617/2009, EXPL/BIM-MEC/0239/2012]
- National Ataxia foundation
- Ataxia UK
- National Institutes of Health (NIH) [GM038109, GM081192, AG026647, NS047331]
- Chicago Biomedical Consortium
- Ellison Medical Foundation
- FCT [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, SFRH/BD/51059/2010]
- POPH
- QREN
- Governo da Republica Portuguesa
- EU/FSE
- Fundação para a Ciência e a Tecnologia [SFRH/BD/84650/2012, SFRH/BPD/91562/2012, SFRH/BD/76613/2011, SFRH/BD/78388/2011, SFRH/BD/78554/2011, SFRH/BPD/74452/2010, SFRH/BD/51059/2010, EXPL/BIM-MEC/0239/2012, PTDC/SAU-GMG/112617/2009, SFRH/BPD/79469/2011] Funding Source: FCT
- Ataxia UK [7270] Funding Source: researchfish
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.
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