Exploring the Role of Citalopram in Treating Spinocerebellar Ataxia Type 3 (SCA3)

Research into the treatment of Spinocerebellar Ataxia Type 3 (SCA3), a progressive neurodegenerative disorder, has yielded promising results with citalopram, a selective serotonin reuptake inhibitor (SSRI). Significantly, the initial breakthrough for citalopram’s potential in treating SCA3 was identified through unbiased small molecule screening using the model organism, Caenorhabditis elegans.

This pioneering research, lead by Dr. Andreia Teixeira-Castro and Dr. Patrícia Maciel at the University of Minho, employed a transgenic C. elegans model expressing the mutant ataxin-3 protein associated with SCA3. The simplicity and genetic tractability of C. elegans allowed for a high-throughput, unbiased screen of various compounds, ultimately identifying citalopram as a candidate that could rescue the motility of these nematodes.

This foundational research highlighted the serotonin transporter (SERT) as a novel therapeutic target for SCA3. Further studies demonstrated that citalopram could suppress mutant ataxin-3 aggregation and alleviate neuronal dysfunction, which was corroborated by subsequent experiments in more complex animal models. Chronic treatment with citalopram was shown to improve motor symptoms reinforcing its therapeutic potential.

The journey of citalopram from initial discovery in C. elegans to validation in higher organisms exemplifies the power of unbiased approaches and simple model organisms in accelerating drug discovery. This strategy not only facilitated the rapid identification of a promising therapeutic but also paved the way for new avenues in the treatment of neurodegenerative diseases such as SCA3.

Teixeira-Castro A, Jalles A, Esteves S, Kang S, da Silva Santos L, Silva-Fernandes A, Neto MF, Brielmann RM, Bessa C, Duarte-Silva S, Miranda A, Oliveira S, Neves-Carvalho A, Bessa J, Summavielle T, Silverman RB, Oliveira P, Morimoto RI, Maciel P. Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain. 2015 Nov;138(Pt 11):3221-37. doi: 10.1093/brain/awv262.