Drug repurposing of dopaminergic drugs to inhibit ataxin-3 aggregation

Abstract

The accumulation of mutant ataxin-3 (Atx3) in neuronal nuclear inclusions is a pathological hallmark of Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia Type 3. Decreasing the protein aggregation burden is a possible disease-modifying strategy to tackle MJD and other neurodegenerative disorders for which only symptomatic treatments are currently available. We performed a drug repurposing screening to identify inhibitors of Atx3 aggregation with known toxicological and pharmacokinetic profiles. Interestingly, dopamine hydrochloride and other catecholamines are among the most potent inhibitors of Atx3 aggregation in vitro. Our results indicate that low micromolar concentrations of dopamine markedly delay the formation of mature amyloid fibrils of mutant Atx3 through the inhibition of the earlier oligomerization steps. Although dopamine itself does not cross the blood-brain barrier, dopamine levels in the brain can be increased by low doses of dopamine precursors and dopamine agonists commonly used to treat Parkinsonian symptoms. In agreement, treatment with levodopa ameliorated motor symptoms in a C. elegans model of MJD. These findings suggest a possible application of dopaminergic drugs to halt or reduce Atx3 accumulation in the brains of MJD patients.

Keywords: Amyloid; Ataxia; Catecholamines; Ciclopirox (PubChem CID: 2749); Dopamine; Dopamine hydrochloride (PubChem CID: 65340); Levodopa (PubChem CID: 6047); Parkinsonian; Pentetic Acid (PubChem CID: 3053); Polyglutamine; Rare Disease; Secondary nucleation; Spinocerebellar ataxia type-3; Tolcapone (PubChem CID: 4659569).