Mechanisms of neuronal cell death in synucleinopathies

 描述(由申请人提供)：联体核病是一组临床上重要的进行性神经疾病，目前还没有批准的治疗方法可以减缓、阻止或逆转进展。这些疾病的定义是在神经突起和细胞体内存在α-突触核蛋白的异常聚集，称为路易氏病理。路易氏包涵体存在于发生细胞死亡的大脑区域，但目前尚不清楚它们与疾病的关系。最近在小鼠模型中使用复杂的、新的活体成像方法的初步数据表明，路易氏病理是在与重组产生的α-突触核蛋白纤维种植后，神经元的内源性α-突触核蛋白形成的。此外，在这些模型中，只有形成路易氏包涵体的神经元注定会死亡。然而，关键的问题仍然存在，包括人类路易氏病理是否由类似的机制形成，以及人类神经元是否也通过与纤维种子小鼠模型相似的途径死亡。为了回答这些问题，将使用先进的电子显微镜(EM)方法。长期目标是确定携带路易氏包涵体的细胞在人类疾病中是如何退化的，以指导阻止这一过程的治疗方法的开发。这项提议将检验核心假设，即在纤维种子小鼠模型和患有帕金森症的人类中，路易包涵体的特定结构和分子特性驱动相关神经细胞死亡。这将在三个具体目标中进行测试：1)确定预测细胞死亡的路易包涵体结构和分子特征。2)确定路易氏包涵体神经元的程序性死亡方式。3)检测路易氏包涵体性质的改变是否是侵袭性神经变性的基础。这项拟议的研究将在俄勒冈健康与科学大学与梅奥诊所和宾夕法尼亚大学的顾问合作进行，这两所大学都在EM方法方面拥有互补的专业知识，以研究大脑疾病和帕金森症的神经病理学。K02-独立科学家奖将为候选人提供研究路易氏病理与神经变性的这种关系所需的高级EM方法方面的专业知识。它还将包括各种有组织的课程、研讨会和正式的咨询计划，以便为开始独立的研究生涯提供良好的基础。最终，所获得的知识有可能导致新的治疗策略，以治疗帕金森氏症、路易体痴呆和相关疾病的方式针对细胞死亡。

 DESCRIPTION (provided by applicant): Synucleinopathies are a group of clinically important, progressive neurological illnesses for which there are no approved therapies that can slow, halt or reverse progression. These diseases are defined by the presence of abnormal aggregates of the protein α-synuclein within neurites and cell bodies, known as Lewy pathology. Lewy inclusions are found in brain regions where cell death occurs, but it is not clear how they relate to disease. Recent preliminary data in mouse models using sophisticated, new in vivo imaging approaches suggests that Lewy pathology forms out of the neuron's endogenous α-synuclein after seeding with recombinant produced α-synuclein fibrils. Furthermore, only neurons that develop Lewy inclusions are fated to die in these models. Critical questions remain, however, including whether human Lewy pathology is formed by similar mechanisms and if human neurons also die by similar pathways as those in fibril-seeded mouse models. In order to answer these questions, advanced electron microscopic (EM) approaches will be used. The long-term goal is to determine how Lewy inclusion-bearing cells degenerate in human disease in order to guide the development of therapies to halt this process. This proposal will test the central hypothesis that specific structural and molecular properties of Lewy inclusions drive associated neuronal cell death in fibril- seeded mouse models and humans with Parkinsonism. This will be tested in three specific aims: 1) Determine the Lewy inclusion structural & molecular characteristics that predict cell death. 2) Determine the mode of programmed cell death in Lewy inclusion-bearing neurons. 3) Test whether alteration of Lewy inclusion properties underlies aggressive forms of neurodegeneration. The proposed study will be conducted at Oregon Health & Science University in collaboration with consultants at the Mayo Clinic and the University of Pennsylvania, each with complementary expertise in EM approaches to study brain disease and the neuropathology of Parkinsonism. This K02 - Independent Scientist Award will provide the candidate with the expertise in advanced EM approaches needed to study this relationship of Lewy pathology to neurodegeneration. It will also involve a variety of structured coursework, workshops and formal advising programs in order to provide an excellent foundation for launching an independent research career. Ultimately, the knowledge gained has the potential to lead to new therapeutic strategies that target cell death in ways that treat Parkinson's disease, Dementia with Lewy Bodies and related disorders.