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

帕金森病(PD)是一种神经退行性疾病，在美国至少有100万人受到影响，它已经 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裹体聚集在刘易体和刘易神经突起中，导致 周围和整个神经轴包括黑质纹状体系统的进行性变性 它调节了这种疾病的主要症状。由于疾病的异质性，在治疗之前 策略可以得到公平的测试，关键是识别和检查PD的特定亚型，作为不同形式的 帕金森病的发病机制可能既不同又有重叠。基因突变 葡萄糖脑苷酶(GBA)基因是帕金森病最常见的遗传危险因素。临床上，GBA突变 帕金森病携带者比非突变携带者运动功能下降更严重，患痴呆症更快 和警察在一起。同时，具有gba突变的帕金森病患者也有更快的α积累和传播。 突触核蛋白。GBA突变、快速以及运动性和非运动性衰退之间的关系 广泛分布的α-突触核蛋白积聚，仍有待明确阐明，其理解可能与 对散发性帕金森病也是如此。这项应用旨在确定侵袭性病理和运动表型 GBA突变携带者帕金森病的原因是：1)宿主GCase酶活性降低和/或2)特定菌株 Gba突变携带者特有的聚集型α-突触核蛋白导致增强的α-突触核蛋白增殖和 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 Gba1D409V/D409V小鼠模型中侵袭性α-SYN的繁殖和更具侵袭性的功能衰退 与野生型小鼠相比。这个突变的小鼠模型，就像患有帕金森病的GBA突变携带者一样，已经减少了 GCase酶活性。我们推测野生型HuPFF注射入Gba1D409V/D409V小鼠的OB内 将会增加α-突触核蛋白的繁殖以及功能运动和认知进展 野生型老鼠。在目标2中，我们将比较GBA和WT PFF在结构和功能上的影响 野生型小鼠的α-syn病理学研究进展。我们假设GBA PFF注射到OB中 野生型小鼠将导致α-突触核蛋白繁殖增加以及功能运动和认知进展 与野生型PFF注射进行比较。我们有独特的能力来检验这个假设，就像我们的实验室所做的那样 展示跨神经元α-突触核蛋白传播的关键工作。建议进行这项研究的理由 一旦我们确定了α-突触核蛋白的传播机制以及功能运动和认知 在我们的模型中，我们将把这些知识应用于预防α-突触核蛋白的新疗法 GBA关联PD的传播。这项拟议的研究还将为旨在 了解α-突触核蛋白菌株如何在多发性骨髓瘤的病理和临床表现中起作用 多种α-突触核病，包括帕金森病、多发性硬化症和多发性硬化症。

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.