How alpha-Synuclein misfolding promotes tau pathology in ADRD

α-突触核蛋白错误折叠如何促进 ADRD 中的 tau 病理学

基本信息

批准号：
10285807
负责人：
Jonathan N Sachs
金额：
$ 37.73万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10285807
关键词：
Administrative Supplement Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Award Behavior Binding Sites Biological Biological Assay Biology Biophysics Biosensor Cell model Cells Chemicals Clinical Research Collaborations Color Complex Coupled Data Dementia with Lewy Bodies Disease Down Syndrome Engineering Environment Fluorescence Fluorescence Resonance Energy Transfer Foundations Frontotemporal Dementia Grant Homo Human Investigation Kinetics Label Lead Letters Lewy Bodies Lewy Body Disease Measurement Methods Microscopy Minnesota Molecular Monitor Morphologic artifacts Nature Neurodegenerative Disorders Neurologist Neurons Outcome Paper Parents Parkinson&apos s Dementia Pathogenesis Pathologic Pathology Phenotype Positioning Attribute Presenile Alzheimer Dementia Prognosis Proteins Protocols documentation Publications Recording of previous events Reproducibility Research Research Personnel Resolution Science Severities Signal Transduction Structure Subgroup System Tauopathies Techniques Technology Testing Time Total Internal Reflection Fluorescent Toxic effect Universities Work alpha synuclein base biophysical tools comorbidity design drug discovery induced pluripotent stem cell inhibitor/antagonist insight kinetic model mouse model mutant neuropathology novel strategies parent grant protein misfolding real time monitoring research study screening small molecule small molecule inhibitor support network synucleinopathy tau Proteins tau aggregation tau interaction tool

项目摘要

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.

抽象的该AD和ADRD研究alpha-synclein的行政补充奖的家长奖（ASYN）使用最先进的技术（荧光寿命品格， 19F-NMR和TIRF显微镜）。在这里，我们将使用这些相同的技术来了解 Asyn和Tau。这些数据将为病理ASYN/TAU相互作用提供至关重要的见解。有助于包括LBD和FTLD在内的各种ADRD蛋白质病的合并症。这个扩展原始研究将使我们的小组从突触病变到Tauopathy研究 - 非常直接，不需要新的材料或方法，而是回答令人兴奋的新问题。神经退行性疾病是根据其主要蛋白质病（例如或 α-核酸）。在tauopathies中，通常会出现错误折叠的tau（例如低聚物，PHF和NFTS）与合并症的合并症蛋白质病在AD和ADRD之间有所不同，并直接合并症与逆境预后相关。忽略这些合并的蛋白质可能阻碍了我们的了解疾病发病机理。在最近的临床研究比较中，α-核蛋白（ASYN） AD的合并症被描述为LBD的重要生物亚组。这种合并症涵盖了广泛的疾病的分布，甚至出现在未衰老的情况下。特定于AD，富含Asyn的Lewy身体（LB）在大多数零星AD病例（约60％），家庭AD病例（超过60％）和AD病例中观察到患有唐氏综合症（超过50％）。相反，AD神经病理学似乎有助于出现 PD和DLB中的痴呆症；潜在地与ASYN协同作用以传播ASYN相关的病理。促使这项工作的假设是AD及相关的Tau和Asyn病理的合并症包括LBD和FLTD在内的痴呆症与Tau在早期与Asyn相互作用的承诺直接相关阶段的寡聚复合物，在不溶性原纤维聚集体之前形成。在此补充中，我们将测试特定的假设是，早期亚裔寡聚物从根本上改变了细胞中的tau结构生物物理学，并且这些变化是病理学中重要的确定剂（因此是目标）。尚无关于Asyn和Tau如何在不折叠的早期阶段共融合的生物物理数据细胞，在原纤维形成之前，也不是这些相互作用如何增加聚集体的毒性。父母赠款使用我们先前确定的荧光寿命生物传感器专注于同性恋相互作用（例如Asyn-Asyn）在引起剧核病的有毒的非纤维寡聚物中。在此补充中，我们将使用我们的生物传感器定义了ASYN和TAU之间异质体相互作用的生物物理基础在陶氏病中，这些相互作用如何导致共聚物以及它们如何影响tau病理学。