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Neurotoxicity of oligomers of phosphorylated Tau protein carrying tauopathy-associated mutation is inhibited by prion protein
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 6.2 ) Pub Date : 2021-07-08 , DOI: 10.1016/j.bbadis.2021.166209
Hanna Nieznanska 1 , Solomiia Boyko 1 , Robert Dec 2 , Maria Jolanta Redowicz 1 , Wojciech Dzwolak 2 , Krzysztof Nieznanski 1
Affiliation  

Tauopathies, including Alzheimer's disease (AD), are manifested by the deposition of well-characterized amyloid aggregates of Tau protein in the brain. However, it is rather unlikely that these aggregates constitute the major form of Tau responsible for neurodegenerative changes. Currently, it is postulated that the intermediates termed as soluble oligomers, assembled on the amyloidogenic pathway, are the most neurotoxic form of Tau. However, Tau oligomers reported so far represent a population of poorly characterized, heterogeneous and unstable assemblies. In this study, to obtain the oligomers, we employed the aggregation-prone K18 fragment of Tau protein with deletion of Lys280 (K18Δ280) linked to a hereditary tauopathy. We have described a new procedure of inducing aggregation of mutated K18 which leads either to the formation of nontoxic amyloid fibrils or neurotoxic globular oligomers, depending on its phosphorylation status. We demonstrate that PKA-phosphorylated K18Δ280 oligomers are toxic to hippocampal neurons, which is manifested by loss of dendritic spines and neurites, and impairment of cell-membrane integrity leading to cell death. We also show that N1, the soluble N-terminal fragment of prion protein (PrP), protects neurons from the oligomers-induced cytotoxicity. Our findings support the hypothesis on the neurotoxicity of Tau oligomers and neuroprotective role of PrP-derived fragments in AD and other tauopathies. These observations could be useful in the development of therapeutic strategies for these diseases.



中文翻译:

携带 tau 蛋白病相关突变的磷酸化 Tau 蛋白寡聚体的神经毒性受朊病毒蛋白抑制

Tauopathies,包括阿尔茨海默病 (AD),表现为大脑中充分表征的 Tau 蛋白淀粉样蛋白聚集体的沉积。然而,这些聚集体不太可能构成导致神经退行性变化的 Tau 的主要形式。目前,假设被称为可溶性低聚物的中间体组装在淀粉样蛋白生成途径上,是 Tau 最具神经毒性的形式。然而,迄今为止报道的 Tau 低聚物代表了一群特征不佳、异质和不稳定的组装。在这项研究中,为了获得寡聚物,我们使用了 Tau 蛋白的易于聚集的 K18 片段,其中缺失与遗传性 tau 蛋白病相关的 Lys280 (K18Δ280)。我们描述了一种诱导突变 K18 聚集的新程序,根据其磷酸化状态,该程序会导致无毒淀粉样蛋白原纤维或神经毒性球状寡聚体的形成。我们证明 PKA 磷酸化的 K18Δ280 寡聚体对海马神经元有毒,表现为树突棘和神经突的丢失,以及导致细胞死亡的细胞膜完整性受损。我们还表明 N1,朊病毒蛋白 (PrP) 的可溶性 N 端片段,保护神经元免受寡聚体诱导的细胞毒性。我们的研究结果支持关于 Tau 寡聚体的神经毒性和 PrP 衍生片段在 AD 和其他 tauopathies 中的神经保护作用的假设。这些观察结果可能有助于开发这些疾病的治疗策略。

更新日期:2021-07-22
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