低温电子显微镜结构揭示了唐氏综合症患者的 tau 纤维采用阿尔茨海默病的折叠结构。

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-06-12 DOI:10.1186/s40478-024-01806-y
Ujjayini Ghosh, Eric Tse, Hyunjun Yang, Marie Shi, Christoffer D Caro, Feng Wang, Gregory E Merz, Stanley B Prusiner, Daniel R Southworth, Carlo Condello
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引用次数: 0

摘要

唐氏综合征(DS)是由 21 号染色体三体综合征引起的一种常见遗传病。唐氏综合征患者具有复杂的临床特征,包括肌肉骨骼、神经和心血管方面的残疾,而且患进行性痴呆和早发性阿尔茨海默病(AD)的风险也会增加。这种痴呆症是由于淀粉样蛋白-β(Aβ)前体蛋白基因的基因剂量增加、Aβ和tau朊病毒构象的自我传播形成、以及具有神经毒性的Aβ斑块和tau神经纤维缠结的沉积造成的。Tau 淀粉样蛋白纤维此前已被证实在不同的神经退行性疾病中具有多种不同的构象。在此,我们报告了利用构象特异性染料和冷冻电镜(cryo-EM)对四例年龄在36-63岁之间的DS患者的脑样本进行光谱共聚焦成像的特征描述,以确定分离的tau纤维的结构。高分辨率结构显示了tau的成对螺旋丝(PHF)和直丝(SF)构象,这些构象与从AD病例中确定的构象完全相同。PHF和SF由两条C形原纤维组成,每条原纤维都包含一个交叉β/β-螺旋图案。与AD病例中的细丝相似,DS病例中的大多数细丝采用PHF形式,而少数(约20%)形成SF。没有痴呆症记录的最年轻个体的样本中tau沉积稀少。为了从这一具有挑战性的样本中分离出 tau 进行低温电子显微镜分析,我们使用了一种新颖的亲和格栅方法,该方法涉及用抗 tau 抗体衍生的氧化石墨烯表面。这种方法提高了分离效果,并发现在这个最年轻的病例中,主要存在tau PHFs和少量慢性创伤性脑病II型样丝。这些发现将AD和DS的相似性扩展到了分子水平,使人们对它们的相关病理有了更深入的了解,并有可能通过小分子疗法和诊断方法靶向共同的tau丝褶皱。
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Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer's disease fold.

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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