Advancing Our Understanding of Oligomer Toxicity in Age-Related Amyloid Disorders

 描述(申请人提供)：淀粉样变性疾病是一组高度多样化的退行性疾病，以这些疾病的组织病理学特征--交叉片状聚集体或淀粉样原纤维命名。突出的例子包括阿尔茨海默病、帕金森氏病、肌萎缩侧索硬化症，以及全身性转甲状腺素和轻链淀粉样变性。特定疾病中的淀粉样蛋白纤维通常由一种特定的蛋白质组成。30多种不同蛋白质中的一种聚集在一起，与一系列病理有关。通常，这些蛋白质在个体的一生中都会表达，但错误折叠、聚集和积累只有在较老的年龄才会表达。受影响组织中淀粉样蛋白结构的不变导致了“淀粉样蛋白假说”的提出，即蛋白质聚集的过程通过有毒的功能获得机制导致组织退化的想法。然而，蛋白质聚集和组织退化之间的机制联系尚不清楚。淀粉样蛋白结构可以在受影响的个体中大量存在，而不会引起症状。因此，领先的，但仍然极具争议性的假说假设，错误折叠的蛋白质的小而可溶的寡聚聚集体是毒性级联的驱动因素。该项目的目的是通过研究从甲状腺激素淀粉样变性患者中分离出来的低聚物，仔细研究低聚物毒性假说，并深入了解低聚物毒性的机制。重要的是，这是监管机构批准的唯一一种可用于阻止疾病进展的抗淀粉样变性药物。因此，可以重复从症状前和有症状的患者以及接受抗淀粉样变治疗的患者那里获取血液样本。我将免疫分离和鉴定患者来源的转甲状腺素低聚物，并使用转录组学和蛋白质组学(K99)破译在原代组织培养中激活的细胞毒性途径。下一步将是在体内探索这些发现，将获得的知识扩展到最常见的与年龄相关的神经退行性疾病，即阿尔茨海默氏症和帕金森氏病，并评估干扰已披露的通路的治疗潜力(R00)。这些结果预计将产生重要的积极影响，因为它们全面描述了寡聚蛋白聚集体对组织退化的贡献，并有望指导该领域努力开发有效、有针对性和成功的治疗老年性淀粉样变性疾病的疗法。

 DESCRIPTION (provided by applicant): Amyloid diseases are a group of highly diverse degenerative disorders, named after the cross-ß-sheet aggregates or amyloid fibrils that are the histopathological hallmarks of these maladies. Prominent examples include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, as well as the systemic transthyretin and light chain amyloidoses. Amyloid fibrils in a given disease generally comprise one specific protein. Aggregation of one of more than 30 different proteins is linked to a spectrum of pathologies. Typically, these proteins are expressed throughout the lifetime of an individual, but misfold, aggregate and accumulate only at an older age. The invariant presence of amyloid structures in affected tissue has led to the formulation of the "amyloid hypothesis", i.e., the idea that the process of protein aggregation causes tissue degeneration by a toxic gain-of-function mechanism. However, the mechanistic connection between protein aggregation and tissue degeneration is not understood yet. Amyloid structures can be present in fairly large quantities in affected individuals without causing symptoms. Therefore, the leading, but still highly controversial hypothesis postulates that small, soluble oligomeric aggregates of the misfolded proteins are drivers of the toxicity cascade. The objective of the proposed project is to scrutinize the oligomer toxicity hypothesis and to gain insight into the mechanism of oligomer toxicity by studying oligomers isolated from patients with transthyretin amyloidosis. Importantly, this is the only amyloid disease where a regulatory agency approved anti-amyloidogenic drug that halts disease progression is available. It is therefore possible to repeatedly obtain blood samples from presymptomatic and symptomatic patients, as well as from patients undergoing anti-amyloidogenic treatment. I will immunoisolate and characterize patient-derived transthyretin oligomers and decipher the cytotoxicity pathways activated in primary tissue cultures using transcriptomics and proteomics (K99). The next step will then be to probe these findings in vivo, to expand the knowledge gained to the most common age-related neurodegenerative disorders, namely Alzheimer's and Parkinson's diseases, and to evaluate the therapeutic potential of interference with the disclosed pathways (R00). The outcomes are expected to have an important positive impact because they comprehensively delineate the contribution of oligomeric protein aggregates to tissue degeneration and are anticipated to guide the field in its endeavor to develop effective, targeted and successful therapeutics for age-related amyloid disorders.