Abstract
The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.
Highlights
Using a drug repurposing approach, we previously identified citalopram, a Selective Serotonin Reuptake Inhibitor (SSRI), as a hit compound capable of reducing the proteotoxicity of mutant ATXN3 in Caenorhabditis elegans (C. elegans) and mice [8,9], suggesting that the modulation of the serotoninergic system exerts a positive role in Machado–Joseph disease (MJD)
In order to evaluate the effect of aripiprazole on mutant ATXN3-mediated proteotoxicity, we used a C. elegans model of Machado–Joseph disease (MJD) pathogenesis, previously generated and characterized in our laboratory
We considered that aripiprazole was safe if animals treated at a particular concentration revealed a rate of food consumption similar to that of control animals treated with DMSO 1%
Summary
Machado–Joseph disease (MJD), known as spinocerebellar ataxia type 3 (SCA3), is a neurodegenerative disease that belongs to the group of the dominantly inherited ataxias [1,2]. The major clinical feature of MJD is progressive ataxia, a progressive lack of motor coordination related to cerebellar and brainstem deterioration (reviewed in [3]). MJD is caused by an aberrant expansion of the CAG trinucleotide in the ataxin-3 (ATXN3). Gene-coding region, which translates into an abnormal polyglutamine (polyQ) tract in the ATXN3 protein [4,5]. This facilitates ATXN3 misfolding and oligomerization, which
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