DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer's Disease-Down Syndrome Phenotypes.
DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer's Disease-Down Syndrome Phenotypes.
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DOI：
10.3389/fphar.2022.881385
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发表时间：
2022
影响因子：
5.6
通讯作者：
Hodge, James J. L.
中科院分区：
文献类型：
--
作者：
Zhu, Bangfu;Parsons, Tom;Stensen, Wenche;Mjoen Svendsen, John S.;Fugelli, Anders;Hodge, James J. L.
阿尔茨海默病（AD）是最常见的神经退行性疾病，由于人口老龄化而变得越来越普遍，给社区带来了巨大的社会、经济和卫生成本。尽管几十年来人们已经知道，淀粉样蛋白前体蛋白（APP）等基因的病理加工可以转化为淀粉样蛋白-β和微管相关蛋白Tau （MAPT）基因，也可以转化为过度磷酸化的Tau缠结，但仍然没有治疗方法可以阻止疾病的进展。患有唐氏综合症（DS）的人群是AD风险增加的人群之一，由于人类21号染色体三体（HSA21）导致APP和其他AD相关基因（如DYRK1A（双特异性酪氨酸磷酸化调节激酶1A）过表达）的三拷贝，唐氏综合症（DS）患者的AD终生发病率为90%。这表明阻断DYRK1A可能具有治疗潜力。然而，目前尚不清楚DYRK1A本身过表达在多大程度上导致ad样表型，以及这些表型与Tau和淀粉样蛋白-β介导的病理如何比较。同样，我们也不知道DYRK1A拮抗剂在预防或改善Tau、淀粉样蛋白-β和DYRK1A介导的表型方面有多有效。为了解决这些悬而未决的问题，我们用靶向过表达人类Tau蛋白、人类淀粉样蛋白-β或DYRK1A的果蝇同源物minibrain （mnb）来表征果蝇模型。我们发现，这些ad相关基因的靶向过表达会导致光感受器神经元的退化、寿命缩短，以及运动能力、睡眠和记忆的丧失。用实验性DYRK1A抑制剂PST-001治疗可降低人Tau的病理性磷酸化[丝氨酸(S) 262]。PST-001减少了由人类Tau、淀粉样蛋白-β或mnb引起的变性，延长了寿命，并改善了由这些AD和DS基因表达引起的运动、睡眠和记忆丧失。这证明了PST-001作为针对AD和DS病理的潜在新治疗方法的有效性。
Alzheimer’s disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as Amyloid Precursor Protein (APP) into Amyloid-β and Microtubule Associated Protein Tau (MAPT) gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of APP and other AD-associated genes, such as DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-β mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-β and DYRK1a mediated phenotype. To address these outstanding questions, we characterised Drosophila models with targeted overexpression of human Tau, human Amyloid-β or the fly orthologue of DYRK1A, called minibrain (mnb). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau [at serine (S) 262]. PST-001 reduced degeneration caused by human Tau, Amyloid-β or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology.
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3.5
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