How alpha-Synuclein misfolding promotes tau pathology in ADRD

摘要 AD和ADRD研究的行政副刊的父奖-α-突触核蛋白 (ASyn)使用最先进的技术(荧光寿命FRET， 19F-核磁共振和TIRF显微镜)。在这里，我们将使用这些相同的技术来理解 ASyn和tau。这些数据将为病理性的aSyn/tau相互作用提供至关重要的见解 导致各种ADRD蛋白病的共病，包括LBD和FTLD。这是对 原创性研究--这将推动我们的团队从联核症研究转向直立神经病研究--相当不错 直截了当，不需要新的材料或方法，但回答令人兴奋的新问题。 神经退行性疾病根据其主要的蛋白质病(例如，神经退行性疾病或 阿尔法-突触核病)。在tauopy病中，错误折叠的tau(例如齐聚物、PHF和NFTs)通常出现 有一种共病蛋白病，在AD和ADRDS中不同，共病的严重程度直接 与不良预后有关。忽视这些并存的蛋白病变可能会阻碍我们的 对疾病发病机制的认识。在最近的一项临床研究比较中，α-突触核蛋白(ASyn) 阿尔茨海默病的共病被描述为LBDS的一个重要生物学亚群。这种共同发病的范围很广。 疾病的分布，甚至在未受损的衰老中也存在。特异于AD，富含Syn的路易小体(LB) 在大多数散发性AD病例(约60%)、家族性AD病例(超过60%)和AD病例中观察到 唐氏综合征(超过50%)。相反，阿尔茨海默病的神经病理似乎有助于 PD和DLB中的痴呆；可能与aSyn协同作用，传播aSyn相关的病理。 支持这项工作的假设是，tau和aSyn病理在AD及其相关疾病中的共同发病率 痴呆，包括LBD和FLTD，与tau在早期与aSyn互动的倾向直接相关- 在不溶性纤维聚集之前形成的阶段性低聚复合体。在本补充资料中，我们将测试 早期aSyn寡聚体从根本上改变细胞中tau结构生物物理的特定假设，以及 这些变化是病理学中的一个重要决定因素(因此也是靶点)。 目前还没有生物物理数据表明aSyn和tau是如何在错误折叠的早期阶段混合在一起的 细胞，在纤维形成之前，也不知道这些相互作用如何增加聚集体的毒性。家长助学金 使用我们之前建立的荧光寿命FRET生物传感器来关注同源-寡聚相互作用 (例如，aSyn-aSyn)在有毒的、非纤维状低聚物中，会导致联体核病。在本增刊中，我们将使用 我们的生物传感器定义了a Syn和tau之间如何形成杂寡体相互作用的生物物理基础 在tau病中，这些相互作用如何导致共寡聚，以及它们如何影响tau病理。

Abstract The parent award to this Administrative Supplement for AD and ADRD research studies alpha-Synuclein (aSyn) oligomerization in great biophysical detail, using state-of-the-art techniques (fluorescence lifetime FRET, 19F-NMR and TIRF microscopy). Here, we will use these same techniques to understand interactions between aSyn and tau. These data will provide critically important insights into the pathological aSyn/tau interaction that contributes to co-morbidities of various ADRD proteinopathies, including LBD and FTLD. This extension of the original research—which will propel our groups from synucleinopathy to tauopathy research—is quite straightforward, requiring no new materials or methods, but answering exciting new questions. Neurodegenerative diseases are classified based on their predominant proteinopathy (e.g. tauopathies or alpha-synucleinopathies). In tauopathies, misfolded tau (e.g. oligomers, PHF, and NFTs) commonly presents with a comorbid proteinopathy that differs across AD and ADRDs with the severity of co-morbidity directly associated with an adverse prognosis. Ignoring these comorbid proteinopathies likely impedes our understanding of disease pathogenesis. In a recent clinical study comparison, alpha-synuclein (aSyn) comorbidity in AD was described as an important biological subgroup of LBDs. This co-morbidity spans a broad distribution of disorders, even being present in unimpaired aging. Specific to AD, aSyn-rich Lewy Bodies (LB) were observed in the majority of sporadic AD cases (around 60%), familial AD cases (over 60%), and AD cases with Down syndrome (over 50%). Conversely, AD neuropathology appears to contribute to the emergence of dementia in PD and DLB; potentially acting synergistically with aSyn to spread aSyn associated pathology. The hypothesis motivating this work is that the co-morbidity of tau and aSyn pathology in AD and related dementias, including LBD and FLTD, is directly associated with tau’s propensity to interact with aSyn in early- stage oligomeric complexes that form before insoluble fibrillar aggregates. In this supplement, we will test the specific hypothesis that early-stage aSyn oligomers fundamentally alter tau structural biophysics in the cell, and that these changes are an important determinant (and hence target) in pathology. No biophysical data yet exists about how aSyn and tau co-mingle in early stages of misfolding in cells, before fibrils form, nor how those interactions increase toxicity of the aggregates. The parent grant uses our previously establish fluorescence lifetime FRET biosensors to focus on homo-oligomeric interactions (e.g. aSyn-aSyn) in toxic, non-fibrillar oligomers that cause synucleinopathies. In this Supplement, we will use our biosensors to define the biophysical basis for how hetero-oligomeric interactions form between aSyn and tau in tauopathies, how these interactions lead to co-oligomerization, and how they impact tau pathology.