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

被引：41

作者：

Teixeira-Castro, Andreia ^{[1
,2
,3
,4
]}

Jalles, Ana ^{[1
,2
]}

Esteves, Sofia ^{[1
,2
]}

Kang, Soosung ^{[3
,5
,6
,7
]}

Santos, Liliana da Silva ^{[1
,2
]}

Silva-Fernandes, Anabela ^{[1
,2
]}

Neto, Mario F. ^{[3
,4
]}

Brielmann, Renee M. ^{[3
,4
]}

Bessa, Carlos ^{[1
,2
]}

Duarte-Silva, Sara ^{[1
,2
]}

Miranda, Adriana ^{[1
,2
]}

Oliveira, Stephanie ^{[1
,2
]}

Neves-Carvalho, Andreia ^{[1
,2
]}

Bessa, Joao ^{[1
,2
]}

Summavielle, Teresa ^{[8
]}

Silverman, Richard B. ^{[3
,5
,6
,7
]}

Oliveira, Pedro ^{[9
]}

Morimoto, Richard I. ^{[3
,4
]}

Maciel, Patricia ^{[1
,2
]}

机构：

[1] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal

[2] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal

[3] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA

[4] Northwestern Univ, Rice Inst Biomed Res, Evanston, IL 60208 USA

[5] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA

[6] Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA

[7] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Evanston, IL 60208 USA

[8] Univ Porto, Inst Biol Mol & Celular, P-4150180 Oporto, Portugal

[9] Univ Porto, ICBAS Abel Salazar Biomed Sci Inst, P-4100 Oporto, Portugal

来源：

BRAIN | 2015年 / 138卷

基金：

美国国家卫生研究院;

关键词：

spinocerebellar ataxia type 3; ataxin; 3; aggregation; therapy; selective serotonin reuptake inhibitor; citalopram; CAENORHABDITIS-ELEGANS; MOUSE MODEL; MUTANT ATAXIN-3; C-ELEGANS; RECEPTOR; MOTOR; CEREBELLAR; NEURONS; STRESS; NEUROTRANSMISSION;

D O I：

10.1093/brain/awv262

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：3221 / 3237

页数：17

共 60 条

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