Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans

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.

Drug repurposing of dopaminergic drugs to inhibit Ataxin-3 aggregation

“…Interestingly, the antipsychotic aripirazole, shown to decrease the levels of polyQ-expanded Atx3 in the brain of MJD transgenic mice without directly interfering with Atx3 fibril assembly in vitro [53], is a partial agonist of dopamine D2 receptors in mammals [54]. Recently, it has been demonstrated that dopamine D2-like receptors are partly responsible for aripiprazole-mediated improvement motor dysfunction in a C. elegans MJD model [55]. A therapeutic strategy relying on low doses of dopaminergic drugs to prevent NNI accumulation would counteract a possible impairment of the nigrostriatal dopaminergic system associated with MJD [56], a feature that was previously identified in both symptomatic and asymptomatic MJD disease gene carriers using single-photon emission computed tomography [57,58].…”

Combinational treatments of RNA interference and extracellular vesicles in the spinocerebellar ataxia

“…However, its complications such as headache and nausea occur in about 50% patients ( Ghanekar et al, 2022 ). Aripiprazole improves dyskinesia but has significant side effects, such as anxiety, nausea, and dizziness ( Jalles et al, 2022 ). The complex pathogenic mechanism and differences between subtypes, patients show the inadequacy of symptomatic treatment ( Yap et al, 2022b ).…”

Quetiapine Shortens the Lifespan of Caenorhabditis elegans through DOP-2, DAF-2 and RSKS-1

“…Aripiprazole, a widely used atypical antipsychotic drug, was shown to extend the lifespan of C. elegans via signaling through DOP-2, a dopamine D2-like receptor (D2R) expressed in worms [ 1 ]. The mechanisms of action of aripiprazole are similar to those of quetiapine, except that quetiapine is a D2R antagonist, whereas aripiprazole possesses an agonistic effect on D2R [ 3 , 4 , 5 ]. Therefore, it is plausible that the lifespan-shortening effect of quetiapine is also mediated by DOP-2.…”