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）在帕金森病和路易体痴呆等神经退行性疾病中可异常聚合形成脑病理包涵体，这些疾病统称为“α-突触核蛋白病”。遗传和神经病理学结果为αS聚集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具有通过类似朊病毒的构象模板机制在细胞内聚集和细胞间扩散的能力。然而，目前尚不清楚是什么生理改变触发了αS包涵病理的初始形成，以及哪些αS变异可能导致了可能解释突触核蛋白病多样性的特征性菌株样传播。我们发现许多生理羧基截断的αS物种表现出更大的自发自聚集倾向，并促进完整αS的聚集。此外，当αS与全长αS结合时，其中一些羧基截断形式的αS更有效地介导αS包裹体的朊病毒样构象模板，但每种羧基截断形式的αS也表现出独特的生化和传播动力学性质。矛盾的是，过量的某些形式的羧基截断αS实际上会降低αS传播病理的能力。利用一系列新的单克隆抗体特异性的羧基截断形式αS，我们最近发表了不同类型的突触核蛋白病的病理包涵体中羧基截断形式αS的神经解剖学分布和相对存在。我们假设这些差异可能是由αS的不同羧基截断形式相关的生物效应驱动的。其中一些αS修饰形式可以产生具有不同传播动力学性质的聚合物，而另一些则可以抑制αS病理的有效神经解剖学传播。为了解决这些关于αS病理进展启动和调节的生物学机制的重要问题，我们提出了以下补充的具体目标：1)我们将利用表达野生型αS的新型人源化小鼠模型，确定人类αS主要生理羧基截断形式启动和增强αS病理传播的倾向。2)我们将确定人类αS主要生理羧基截断形式的存在对种子起始后αS病理传播的调节程度。3)在表达野生型αS的人源化小鼠模型中，我们将确定羧基截断形式αS在多大程度上决定了αS病理传播的活性，并具有独特的菌株样特性，这些特性与独特的组织学和生化特征、神经解剖学分布和神经退行性结局有关。总的来说，这些研究将为αS生理羧基截断形式在调节αS病理的传播和类型方面的功能提供见解，αS病理可能导致各种突触核蛋白病。