Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins

蛋白质错误折叠和聚集形成纤维是神经退行性疾病的常见特征， 包括阿尔茨海默氏症、帕金森氏症和相关的痴呆症，如路易痴呆症 小体和多系统萎缩。逆转或阻断蛋白质聚集的药物，与早期联合 诊断，为保存患者记忆的治愈提供了前景。设计这样的药物和 对于诊断试剂，我们必须了解神经元内聚集和传播的过程才能“感染” 新的神经元来识别最相关的目标。在此资助期内，我们建议使用距离 用荧光和交联探针进行测量以驱动错误折叠的计算模型 和α-突触核蛋白(α，S)和tau蛋白的聚集。我们将不仅模拟单体αS和陶，而且 也指不能通过固体核磁共振(ss核磁共振)或冷冻电子进行表征的聚集态 显微镜(低温电子显微镜)。我们的计算模型将被用来预测小分子的有序结合 验证它们的分子细节，并确定它们在抑制剂设计和诊断中的潜力 探员们。我们的方法也可以用来研究不同错误折叠的αS和tau多态，它们表现出 不同的倾向形成新的纤维和不同程度的细胞毒性。例如，最近对 帕金森氏病的主要聚集者αS已经表明，tau纤维可以由一些 αS纤维的构象形式(“菌株”)，而不是其他的。我们将调查化学尺度的差异 αS菌株之间的结构和某些菌株播种tau原纤维的基础。这将产生重要的影响 帕金森氏病、路易体痴呆和多系统萎缩的病理洞察 也将为其他继发性tau病理的研究奠定基础，例如β种子tau聚集体 阿尔茨海默氏症。

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.