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

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Teixeira Castro, A (Author) Other; Jalles, A (Author) Other; Esteves, S (Author) Other; Kang, S (Author) Other; Santos, LD (Author) Other; Silva Fernandes, A (Author) Other; Neto, MF (Author) Other; Brielmann, RM (Author) Other; Bessa, C (Author) Other; Duarte Silva, S (Author) Other; Miranda, A (Author) Other; Oliveira, S (Author) Other; Neves Carvalho, A (Author) Other; Bessa, J (Author) Other; Summavielle, T (Author) Other; Silverman, RB (Author) Other; oliveira, p (Author) ICBAS; Morimoto, RI (Author) Other; Maciel, P (Author) Other

Journal

Title: Brain

Vol. 138

Pages: 3221-3237

ISSN: 0006-8950

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 9 Citations

Scopus - 47 Citations

Other information

Authenticus ID: P-00G-X13

DOI: 10.1093/brain/awv262

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17