Does alpha synuclein strain or GCase enzyme activity drive clinical aggression in GBA-PD?

α 突触核蛋白菌株或 GCase 酶活性是否会导致 GBA-PD 患者的临床攻击行为？

• 批准号: 9789065
• 负责人: Jeffrey H Kordower
• 金额: $ 23.55万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789065
• 关键词: Affect; Aggressive Clinical Course; Aggressive behavior; Brain; Clinical; Clinical Course of Disease; Cognitive; Dementia; Disease; Disease Progression; Etiology; Genes; Genetic; Human; Idiopathic Parkinson Disease; Impaired cognition; Injections; Intervention; Knowledge; Letters; Lewy Bodies; Mediating; Modeling; Motor; Mus; Mutation; Nature; Neuraxis; Neurites; Neurodegenerative Disorders; Outcome; Parkinson Disease; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Prevalence; Property; Research; Structure; Study models; Symptoms; Testing; Therapeutic; Wild Type Mouse; Work; alpha synuclein; dementia risk; disease heterogeneity; disorder control; enzyme activity; functional decline; genetic risk factor; glucosylceramidase; loss of function; mouse model; mutant mouse model; mutation carrier; nigrostriatal system; novel; prevent; success; synucleinopathy

Parkinson disease (PD) is a neurodegenerative disease affecting at least 1 million people in the U.S. and it has been estimated that 14.6 million people will be affected worldwide by 2040. Pathologic intraneuronal inclusions composed of misfolded α-synuclein accumulate in Lewy bodies and Lewy neurites, resulting in progressive degeneration within the periphery and across the neuraxis including the of the nigrostriatal system which mediates the cardinal symptoms of the disease. Because of disease heterogeneity, before therapeutic strategies can be fairly tested, it is critical to identify and examine specific subtypes of PD, as different forms of PD are likely to have both distinct and overlapping pathogenic mechanisms. Mutations in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for PD. Clinically, GBA mutation carriers with PD have more aggressive motor decline and develop dementia faster than non-mutation carriers with PD. In parallel, PD subjects with GBA mutations also have a more rapid accumulation and spread of α- synuclein. The relationship between GBA mutations, rapid and both motor and non-motor decline, and this wide-spread α-synuclein accumulation, remains to be clearly elucidated and its understanding will likely related to sporadic PD as well. This application aims to define whether the aggressive pathologic and motor phenotype of GBA mutation carriers with PD is due to: 1) reduced host GCase enzymatic activity and/or 2) specific strains of aggregated α-synuclein unique to GBA mutation carriers result in enhanced α-synuclein propagation and functional motor progression in a GBA mouse model. In aim 1, we will determine whether there is more aggressive alpha-syn propagation and more aggressive functional decline in a Gba1D409V/D409V mouse model compared with wild-type mice. This mutant mouse model, like GBA mutation carriers with PD, has reduced GCase enzymatic activity. We hypothesize that wild-type HuPFF injection into the OB in Gba1D409V/D409V mice will have increased α-synuclein propagation and functional motor and cognitive progression compared with wild-type mice. In aim 2, we will compare the effect of GBA vs. WT PFFs on structural and functional progression of alpha-syn pathology in wild-type mice. We hypothesize that GBA PFF injection into the OB in wild-type mice will result in increased α-synuclein propagation and functional motor and cognitive progression compared with wild-type PFF injections. We are uniquely equipped to test this hypothesis as our lab has done critical work in demonstrating transneuronal α-synuclein propagation. The rationale for the proposed research is that once we determine the mechanism of α-synuclein propagation and functional motor and cognitive progression in our model, we will apply this knowledge toward novel treatments to prevent α-synuclein propagation for GBA associated PD. The proposed research will also open the door to new research aimed at understanding how α-synuclein strains contribute to the diverse pathological and clinical presentations of a variety of α-synucleinopathies, including PD, MSA, and DLB.

帕金森病（PD）是一种神经退行性疾病，在美国影响至少100万人， 据估计，到2040年，全球将有1460万人受到影响。病理性神经元内 由错误折叠的α-突触核蛋白组成的包涵体聚集在路易体和路易神经突中，导致 外周内和整个神经轴（包括黑质纹状体系统）的进行性变性 它介导了疾病的主要症状。由于疾病的异质性，治疗前 虽然可以公平地测试策略，但识别和检查PD的特定亚型是至关重要的，因为不同形式的 PD可能具有不同和重叠的致病机制。突变 葡萄糖脑苷脂酶（GBA）基因是PD最常见的遗传危险因素。临床上，GBA突变 与非突变携带者相比，PD携带者的运动功能下降更严重，痴呆发展更快 PD的。与此同时，GBA突变的PD受试者也有更快的α-SMA的积累和扩散。 共核蛋白GBA突变之间的关系，快速和运动和非运动的下降，这 广泛分布的α-突触核蛋白积累，仍有待明确阐明，其理解可能与 也有零星的PD。本申请旨在确定是否侵袭性病理和运动表型 GBA突变携带者的PD是由于：1）宿主GCase酶活性降低和/或2）特异性菌株 GBA突变携带者特有的聚集的α-突触核蛋白导致增强的α-突触核蛋白增殖， GBA小鼠模型中的功能性运动进展。在目标1中，我们将确定是否有更多 Gba 1D 409 V/D409 V小鼠模型中的侵袭性α-syn传播和更具侵袭性的功能下降 与野生型小鼠相比。这种突变小鼠模型，像患有PD的GBA突变携带者一样， GCase酶活性。我们假设将野生型HuPFF注射到Gba 1D 409 V/D409 V小鼠的OB中， 将增加α-突触核蛋白的传播和功能性运动和认知进展， 野生型小鼠。在目标2中，我们将比较GBA与WT PFF对结构和功能的影响。 野生型小鼠中α-syn病理学的进展。我们假设，GBA PFF注入OB， 野生型小鼠将导致α-突触核蛋白增殖和功能性运动和认知进展增加 与野生型PFF注射相比。我们有独特的设备来测试这个假设，就像我们的实验室所做的那样。 证明跨神经元α-突触核蛋白传播的关键工作。拟议研究的理由 一旦我们确定了α-突触核蛋白的传播机制， 在我们的模型中，我们将把这些知识应用于新的治疗方法，以防止α-突触核蛋白 GBA相关PD的传播。拟议中的研究还将为新研究打开大门， 了解α-突触核蛋白菌株如何有助于不同的病理和临床表现， 各种α-突触核蛋白病，包括PD、MSA和DLB。