Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins

蛋白质错误折叠和聚集形成原纤维是神经退行性疾病的常见特征， 包括阿尔茨海默氏病、帕金森氏病和相关的痴呆症，如路易氏痴呆症 身体和多系统萎缩。逆转或阻断蛋白质聚集的药物，结合早期 诊断，为保留病人记忆的治疗提供了前景。设计这样的药物， 诊断剂，必须了解神经元内的聚集过程和传播“感染” 新的神经元来识别最相关的目标。在这段时间里，我们建议利用距离 用荧光和交联探针进行测量，以驱动错误折叠的计算模型 以及α-突触核蛋白（αS）和tau蛋白的聚集。我们将不仅模拟单体αS和tau， 也包括不适合通过固态NMR（ssNMR）或低温电子（cryo-electron）表征的聚集形式 显微镜（cryo-EM）。我们的计算模型将用于预测小分子的结合， 以验证其分子细节，并确定其在抑制剂设计和诊断中的应用潜力。 剂.我们的方法也可用于研究不同的错误折叠的αS和tau多态性，它们表现出 形成新原纤维的不同倾向和不同水平的细胞毒性。例如，最近对 αS是帕金森氏病的主要聚集剂，已经表明tau纤维可以通过一些细胞因子接种。 构象形式（“应变”）的αS纤维，但不是其他。我们将调查化学规模的差异， αS菌株之间的结构和某些菌株接种tau纤维的基础。这将使重要 对帕金森病、路易体痴呆和多系统萎缩的病理学的见解; 还将为其他继发性tau病理学的研究奠定基础，如Aβ-种子tau聚集体 老年痴呆症

Protein misfolding and aggregation to form fibrils are common features of neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, and related dementias such as Dementia with Lewy Bodies and Multiple System Atrophy. Drugs that reverse or block protein aggregation, combined with early diagnosis, provide the prospect for a cure that preserves the patient's memories. To design such drugs and diagnostic agents, one must understand the process of aggregation within neurons and propagation to “infect” new neurons to identify the most relevant targets. In this funding period, we propose to use distance measurements made with fluorescence and crosslinking probes to drive computational models of the misfolding and aggregation of the proteins α-synuclein (αS) and tau. We will model not only monomeric αS and tau, but also aggregated forms that are not amenable to characterization by solid state NMR (ssNMR) or cryo-electron microscopy (cryo-EM). Our computational models will be used to predict the binding of small molecules in order to validate their molecular details and establish their potential for use in the design of inhibitors and diagnostic agents. Our methods can also be used to study different misfolded αS and tau polymorphs, which exhibit different tendencies to form new fibrils and different levels of cytotoxicity. For example, recent investigations of αS, the primary aggregator in Parkinson's Disease, have shown that tau fibrils can be seeded by some conformational forms (“strains”) of αS fibrils, but not others. We will investigate the chemical scale differences in structure between αS strains and the basis for tau fibril seeding by certain strains. This will shed important insight on the pathology of Parkinson's Disease, Dementia with Lewy Bodies, and Multiple System Atrophy; it will also set the stage for investigations of other secondary tau pathologies, such as Aβ-seeded tau aggregates in Alzheimer's Disease.