Mechanisms of Neurodegeneration in Lewy Body Disorders

路易体疾病的神经变性机制

• 批准号: 9362192
• 负责人: Vivek Unni
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362192
• 关键词: Acidic Amino Acids; Apoptosis; Basic Science; Biological Process; Bleomycin; Brain; Breast; C-terminal; Cell Death; Cells; Cessation of life; Chemicals; Comet Assay; Complex; Cytoplasm; DNA Double Strand Break; DNA Repair; Data; Disease; Double Strand Break Repair; Family member; Fluorescence Microscopy; Functional disorder; Gamma synuclein; Genetic; Goals; H2AFX gene; Human; Image; Imaging Techniques; Immunohistochemistry; In Vitro; Knock-out; Knowledge; Lead; Lewy Bodies; Lewy Body Dementia; Link; Liquid substance; Malignant Neoplasms; Mediating; Mus; Mutation; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phase; Play; Poly(ADP-ribose) Polymerases; Population; Process; Proteins; Recruitment Activity; Research; Role; Seeds; Site; Source; Symptoms; Synuclein Family; System; Testing; Time; Tissues; Work; alpha synuclein; ataxia telangiectasia mutated protein; brain cell; disease diagnosis; drug development; human disease; imaging approach; in vitro Assay; in vivo; innovation; loss of function; malignant breast neoplasm; melanoma; mouse model; multiphoton imaging; neuron loss; new therapeutic target; novel; novel therapeutic intervention; protein function; reconstitution; repaired; synucleinopathy

PROJECT SUMMARY One major obstacle to halting neurodegeneration in synucleinopathies like Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB) is a lack of understanding of why vulnerable cell populations die. Although aggregated alpha-synuclein Lewy pathology occurs within specific neurons, and their dysfunction or degeneration leads to symptoms in these diseases, how Lewy pathology itself plays a role is unclear. Recent work by the Unni lab has discovered a previously unrecognized function for the protein alpha-synuclein in repairing nuclear DNA double-strand breaks (DSB), by using newly developed in vivo multiphoton imaging techniques to study alpha-synuclein aggregation in mice. These approaches have now been extended (for the first time) to study DNA repair in living mouse brain. The unexpected function for alpha-synuclein immediately suggests an exciting new hypothesis for the role of aggregated alpha-synuclein Lewy inclusions in neurodegeneration. This central hypothesis is that in disease, alpha-synuclein protein is sequestered in cytoplasmic Lewy bodies, decreasing its nuclear DSB repair function and leading to cell death of Lewy body- containing neurons. Furthermore, it is proposed that the source of fibrillar α-synuclein that initially seeds Lewy body formation comes from dysregulated DSB repair. The preliminary data suggest this complex interrelationship, with alpha-synuclein aggregation causing dysregulated DSB repair and vice versa. Although completely novel, this link between alpha-synuclein and DSB repair could explain previously poorly understood associations between human and mouse mutations in the DSB repair protein Ataxia-Telangiectasia Mutated and alpha-synuclein aggregation, and between specific synuclein family members and cancer (e.g. alpha- synuclein & melanoma, gamma-synuclein & breast cancer). This proposal will use a combination of advanced imaging approaches in purified, reconstituted in vitro systems, in mouse brain in vivo, and in mouse & human (PD, DLB) fixed tissue to test how alpha-synuclein mediates DSB repair (Aim 1), how loss of nuclear α- synuclein function after cytoplasmic Lewy inclusion formation dysregulates DSB repair and contributes to neuronal cell death (Aim 2), and how dysregulated DSB repair can lead to Lewy inclusion formation (Aim 3). Overall, this project is innovative because it uses powerful, new in vivo experimental approaches to test a fundamentally new hypothesis for how alpha-synuclein aggregation into Lewy pathology is related to neurodegeneration. This contribution will be significant because it will provide a completely new set of targets for treating these debilitating neurodegenerative disorders that focuses on the DSB repair pathway, and because understanding alpha-synuclein-mediated DSB repair in detail will increase our basic science knowledge of this important biological process.

项目摘要 阻止突触核蛋白病（如帕金森病（PD））神经变性的一个主要障碍是， 路易体痴呆症（DLB）缺乏对脆弱细胞群死亡原因的理解。虽然 聚集的α-突触核蛋白Lewy病理发生在特定的神经元内，并且它们的功能障碍或 尽管路易氏变性导致这些疾病的症状，但路易氏病理学本身如何发挥作用尚不清楚。最近 Unni实验室的工作发现了蛋白质α-突触核蛋白的一种以前未被认识的功能， 利用新开发的体内多光子成像修复核DNA双链断裂（DSB） 研究小鼠中α-突触核蛋白聚集的技术。这些方法现在已经得到了扩展（对于 第一次）研究活体小鼠大脑中的DNA修复。α-突触核蛋白的意外功能 提出了一个令人兴奋的新假设，即聚集的α-突触核蛋白Lewy包涵体在 神经变性这一中心假设是，在疾病中，α-突触核蛋白被隔离在 细胞质路易体，降低其核DSB修复功能并导致路易体的细胞死亡- 含有神经元。此外，有人提出，最初播种Lewy的纤维状α-突触核蛋白的来源 身体的形成来自DSB修复失调。初步数据显示， 相互关系，与α-突触核蛋白聚集引起DSB修复失调，反之亦然。虽然 这种α-突触核蛋白和DSB修复之间的联系是全新的，可以解释以前很少了解的问题。 DSB修复蛋白共济失调-毛细血管扩张突变中人类和小鼠突变之间的关联 和α-突触核蛋白聚集之间，以及特定突触核蛋白家族成员与癌症（例如α-突触核蛋白聚集）之间的关系。 突触核蛋白和黑素瘤、γ-突触核蛋白和乳腺癌）。该提案将使用先进的 在纯化的、重建的体外系统中、在小鼠体内脑中以及在小鼠和人类中的成像方法 (PD，DLB）固定的组织，以测试α-突触核蛋白如何介导DSB修复（Aim 1），核α-突触核蛋白的丢失如何介导DSB修复（Aim 1）。 胞质Lewy包涵体形成后的突触核蛋白功能失调DSB修复， 神经元细胞死亡（目标2），以及DSB修复失调如何导致Lewy包涵体形成（目标3）。 总的来说，这个项目是创新的，因为它使用了强大的，新的体内实验方法来测试一个 关于α-突触核蛋白聚集到路易病理学中的基本新假设与 神经变性这一贡献将是重大的，因为它将提供一套全新的目标 用于治疗这些集中在DSB修复途径上的衰弱性神经退行性疾病，以及 因为详细了解α-突触核蛋白介导的DSB修复将增加我们的基础科学 了解这一重要的生物学过程。