Testing the multimodal anti-depressant vortioxetine as a therapeutic strategy to mitigate SCA3
Ataxia UK
University of Minho
Spinocerebellar ataxia type 3 (SCA3) is an inherited ataxia, caused by a mutation in the ATXN3 gene. This group previously demonstrated that modulation of serotonin (5-HT) signalling by the selective serotonin reuptake inhibitor, citalopram, suppressed mutant ataxin-3 aggregation and neuronal dysfunction in SCA3 in vivo models. In this work, they established the 5-HT transporter SERT as a novel therapeutic target for SCA3. Moreover, they identified a decrease in the expression of 5-HT1A receptors (5-HT1AR) in transgenic mice, which was restored to WT levels upon chronic citalopram administration. Direct targeting of the 5-HT1AR using a potent agonist (befiradol) also suppressed mutant ataxin-3 pathogenesis. Here, they aim to simultaneously target SERT and 5-HTRs, by using the multimodal antidepressant vortioxetine as a novel therapeutic strategy to mitigate SCA3, potentially increasing therapeutic efficacy previously obtained with citalopram and befiradolalone. They will test vortioxetine in a genetic mouse model of SCA3, and they hypothesise that vortioxetine will protect against mutant ataxin-3-induced neurotoxicity and stall disease progression. This pre-clinical study will inform prospective clinical trials targeting the serotonergic system.
2.1 Biological and endogenous factors