Molecular mechanisms of alpha-synuclein induction and spread of pathobiology

α-突触核蛋白诱导和病理学传播的分子机制

• 批准号: 10560064
• 负责人: BENOIT I GIASSON
• 金额: $ 112.34万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560064
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease patient; Amygdaloid structure; Appendectomy; Biochemical; Biological; Brain; Cells; Characteristics; Cultured Cells; Disease Progression; Endocytosis; Etiology; Experimental Models; Genetic; Genetic study; Histologic; Human; In Vitro; Kinetics; Length; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy body pathology; Lewy neurites; Mediating; Missense Mutation; Modification; Molecular; Molecular Conformation; Monoclonal Antibodies; Multiple System Atrophy; Nerve Degeneration; Nervous System Heredodegenerative Disorders; Neuroanatomy; Neurodegenerative Disorders; Neurons; Oligodendroglia; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Peripheral Nervous System; Physiological; Play; Polymers; Prions; Property; Proteins; Publishing; Reporting; Research Project Grants; Role; Series; Variant; alpha synuclein; autosome; copolymer; early onset; humanized mouse; insight; mouse model; neuropathology; novel; novel therapeutic intervention; presynaptic; prion-like; protein aggregation; synucleinopathy; transmission process

The presynaptic protein α-synuclein (αS) can aberrantly polymerize to form brain pathological inclusions in a spectrum of neurodegenerative diseases, such as Parkinson’s disease and Lewy body dementia, which are collectively termed “α-synucleinopathies”. Genetic and neuropathological findings provide compelling evidence for the toxic role of aggregated αS in disease progression. Studies from our group and many others have demonstrated that αS has the ability to aggregate intracellularly and to spread between cells by conformational templating prion-like mechanisms. However, it is still unclear what physiological alterations trigger the initial formation of αS inclusion pathology and what αS variants might be responsible for characteristic strain-like transmission that might explain the diversity of synucleinopathies. We demonstrated that many of the physiological carboxy-truncated αS species display significantly greater propensity to spontaneously self-aggregate and promote the aggregation of intact αS. Furthermore, some of these carboxy truncated forms of αS are more potent at mediating prion-like conformational templating of αS inclusions when combined with full length αS but each carboxy-truncated forms of αS also display unique biochemical and propagation kinetic properties. Paradoxically the excess of some forms of carboxy-truncated αS can actually reduce the ability of αS to propagate pathology. Using a novel series of monoclonal antibodies specific for carboxy-truncated forms of αS, we recently published that the neuroanatomical distribution and relative presence of carboxy-truncated forms of αS within pathological inclusions differs between different types of synucleinopathies. We hypothesized that these differences may be driven by the biological effects associated with distinct carboxy-truncated forms of αS. Some of these modified forms of αS many yield polymers with varied propagation kinetic properties while others may inhibit effective neuroanatomical propagation of αS pathology. To address these important questions on the biological mechanisms involved in the initiation and modulation of αS pathological progression, we propose the following complementary Specific Aims. 1) We will determine the propensity of the major physiological carboxy-truncated forms of human αS to initiate and potentiate the propagation of αS pathology using a novel humanized mouse model expressing wild type αS. 2) We will determine the extent of which the presence of the major physiological carboxy-truncated forms of human αS can regulate the spread of αS pathology following seeded initiation. 3) We will determine the extent of which carboxy truncated forms of αS dictates the activities to propel the spread of αS pathology with unique strain-like properties associated with distinctive histological and biochemical features, neuroanatomical distribution and neurodegeneration outcomes in our humanize mouse model expressing wild type αS. Collectively, these studies will provide insights on the function of physiological carboxy-truncated forms of αS in modulating the spread and type of αS pathology that can be responsible for the varied spectrum of synucleinopathies.

突触前蛋白α-突触核蛋白(αS)可在一系列神经退行性疾病中异常聚合形成脑内病理性包涵体，如帕金森病和路易体痴呆，统称为α-突触核病症。遗传学和神经病理学的发现为聚集的αS在疾病进展中的毒性作用提供了令人信服的证据。本课题组和其他许多人的研究表明，αS具有细胞内聚集和细胞间扩散的能力，其机制与构象模板类似。然而，目前尚不清楚是什么生理变化触发了αS包涵体病理的初步形成，以及哪些αS变异可能导致了可能解释共核病多样性的特征菌株样传播。我们证明了许多生理性羧基截短的αS物种表现出显著更大的自发自聚集倾向和促进完整αS的聚集。此外，这些羧基截短的αS中的一些当与全长αS结合时更有效地介导了αS包涵体的Pron样构象模板，但每个羧基截短的αS也表现出独特的生化和繁殖动力学性质。矛盾的是，过量的某些形式的羧基截短αS实际上会降低αS传播病理的能力。利用一系列针对羧基截短型αS的新的单抗，我们最近发表了一篇文章，指出不同类型的共核病在病理包涵体中羧基截短型αS的神经解剖分布和相对存在情况有所不同。我们推测，这些差异可能是由不同的羧基截短形式的αS相关的生物学效应驱动的。其中一些修饰形式的αS许多产生具有不同繁殖动力学性质的聚合物，而另一些可能抑制αS病理的有效神经解剖传播。为了解决这些涉及αS病理进展启动和调控的生物学机制的重要问题，我们提出了以下补充的特定目标。1)我们将使用表达野生型αS的新型人源化小鼠模型来确定人αS的主要生理羧基截断形式启动和增强αS病理传播的倾向。2)我们将确定人αS的主要生理羧基截断形式的存在在多大程度上可以调节种子启动后αS病理的传播。3)在我们表达野生型αS的人源化小鼠模型中，我们将确定羧基截短形式的αS在多大程度上决定了推动αS病理传播的活动，具有独特的毒株样属性，与独特的组织学和生化特征、神经解剖分布和神经变性结果相关。总之，这些研究将为生理性截短形式的αS在调控αS病理的传播和类型方面的功能提供见解，这些病理类型可能导致一系列不同的共核病。