How alpha-Synuclein misfolding promotes tau pathology in ADRD

摘要 本行政补充的父奖AD和ADRD研究研究α-突触核蛋白 （aSyn）寡聚化，使用最先进的技术（荧光寿命FRET， 19 F-NMR和TIRF显微术）。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aSyn/tau相互作用提供至关重要的见解， 导致各种ADRD蛋白病的合并症，包括LBD和FTLD。的这种延伸 原创性研究-这将推动我们的团队从突触核蛋白病到tau蛋白病的研究-是相当 简单，不需要新的材料或方法，但回答令人兴奋的新问题。 神经退行性疾病基于其主要蛋白质病（例如，tau蛋白病或Tau蛋白病）进行分类。 α-突触核蛋白病）。在tau蛋白病中，错误折叠的tau蛋白（例如，寡聚体、PHF和NFT）通常存在 AD和ADRD之间的共病蛋白质病不同，共病的严重程度直接 与不良预后相关。忽视这些共病蛋白质病可能会阻碍我们的研究。 了解疾病的发病机制。在最近的临床研究比较中，α-突触核蛋白（aSyn） AD合并症是LBD的一个重要生物学亚组。这种并发症跨越了广泛的 疾病的分布，甚至存在于未受损的衰老中。AD特异性，富含aSyn的路易体（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 唐氏综合症（Down Syndrome），占50%以上。相反，AD神经病理学似乎有助于 PD和DLB中的痴呆;可能与aSyn协同作用以传播aSyn相关病理。 激发这项工作的假设是AD和相关疾病中tau和aSyn病理学的共病性。 痴呆，包括LBD和FLTD，与tau在早期与aSyn相互作用的倾向直接相关。 在不溶性纤维状聚集体之前形成的阶段性低聚复合物。在本附录中，我们将测试 早期aSyn寡聚体从根本上改变细胞中tau结构生物物理学的特定假设，以及 这些变化是病理学中的重要决定因素（因此也是目标）。 目前还没有生物物理学数据表明aSyn和tau在细胞错误折叠的早期阶段是如何混合在一起的。 细胞，在纤维形成之前，也没有这些相互作用如何增加聚集体的毒性。父母补助金 使用我们以前建立的荧光寿命FRET生物传感器，专注于同源寡聚相互作用 (e.g. aSyn-aSyn）在引起突触核蛋白病的毒性、非纤维状寡聚体中。在本补充文件中，我们将使用 我们的生物传感器来定义aSyn和tau之间如何形成异源寡聚相互作用的生物物理基础 在tau蛋白病中，这些相互作用如何导致共寡聚化，以及它们如何影响tau蛋白病。

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.