Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
Biomed Pharmacother. 2023 Sep;165:115258. doi: 10.1016/j.biopha.2023.115258. Epub 2023 Aug 5.
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.
突变型共济失调蛋白 3（Atx3）在神经元核内包涵体中的积累是 Machado-Joseph 病（MJD）的病理学标志，也称为脊髓小脑共济失调 3 型。减少蛋白质聚集负担是一种可能的疾病修饰策略，可以治疗 MJD 和其他目前只有对症治疗的神经退行性疾病。我们进行了药物再利用筛选，以确定具有已知毒理学和药代动力学特征的 Atx3 聚集抑制剂。有趣的是，盐酸多巴胺和其他儿茶酚胺是体外抑制 Atx3 聚集最有效的抑制剂之一。我们的结果表明，低微摩尔浓度的多巴胺通过抑制早期寡聚化步骤，显著延迟突变型 Atx3 成熟淀粉样纤维的形成。尽管多巴胺本身不能穿过血脑屏障，但通过常用的治疗帕金森症状的多巴胺前体和多巴胺激动剂的低剂量，可以增加大脑中的多巴胺水平。一致地，用左旋多巴治疗改善了 MJD 线虫模型中的运动症状。这些发现表明多巴胺能药物可能适用于阻止或减少 MJD 患者大脑中 Atx3 的积累。
