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（α-synuclein，αS）可在帕金森病、路易体痴呆等神经退行性疾病中异常形成病理性包涵体，统称为“α-synucleinopathies”。遗传和神经病理学结果为聚集αS在疾病进展中的毒性作用提供了令人信服的证据。我们小组和其他许多人的研究表明，αS具有在细胞内聚集的能力，并通过构象模板朊病毒样机制在细胞间传播。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变体可能导致特征性菌株样传播，这可能解释了突触核蛋白病的多样性。我们证明，许多生理性羧基截短的αS物质显示出显著更大的自发自聚集倾向，并促进完整αS的聚集。此外，当与全长αS结合时，这些αS的羧基截短形式中的一些在介导αS包涵体的朊病毒样构象模板化方面更有效，但αS的每种羧基截短形式也显示出独特的生物化学和繁殖动力学性质。有趣的是，某些形式的羧基截短αS的过量实际上可以降低αS传播病理的能力。使用一系列新的特异于αS羧基截短形式的单克隆抗体，我们最近发表了神经解剖学分布和病理包涵体中αS羧基截短形式的相对存在在不同类型的突触核蛋白病之间存在差异。我们假设这些差异可能是由与不同的羧基截短形式的αS相关的生物学效应驱动的。这些αS的修饰形式中的一些产生具有不同传播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。为了解决这些关于αS病理进展的启动和调节所涉及的生物学机制的重要问题，我们提出了以下补充性特定目标。1)我们将使用表达野生型αS的新型人源化小鼠模型，确定人αS的主要生理羧基截短形式启动和增强αS病理学传播的倾向。2)我们将确定在接种启动后，人αS的主要生理羧基截短形式的存在可以调节αS病理学扩散的程度。3)我们将在表达野生型αS的人源化小鼠模型中，确定αS羧基截短形式在多大程度上决定了推动αS病理扩散的活性，该病理具有独特的菌株样性质，与独特的组织学和生化特征、神经解剖学分布和神经变性结果相关。总的来说，这些研究将提供关于αS的生理性羧基截短形式在调节αS病理学的传播和类型中的功能的见解，αS病理学可能是导致各种突触核蛋白病的原因。