Role of GlcSph in cognitive deficits in Lewy body dementias

帕金森病痴呆(PDD)和路易体痴呆(DLB)是两种神经退行性疾病 以认知障碍为特征的疾病，包括执行功能障碍、视觉空间处理 困难和工作记忆受损。认知障碍是最令人衰弱的症状之一 这些疾病往往导致制度化和健康严重下降。在帕金森病患者中，认知症状是 通常在诊断时出现，但可在疾病过程中出现。在DLB中，认知发生了变化 首先是运动性帕金森症的发展。这两种疾病统称为路易体 痴呆症的病理特征是含有α-突触核蛋白的聚集体，称为路易 病理学。路易氏病理发现在大脑中对认知有重要作用的区域，包括大脑皮层和 与认知能力下降相关的海马体。基因GBA1的遗传变异也与 有LBDS的。GBA1编码葡萄糖脑苷酶，这是一种代谢葡萄糖神经酰胺的酶。基因突变 葡萄糖脑苷酶降低其酶活性。高达12%的帕金森病病例涉及GBA1基因变异。 约占所有PD-GBA1突变的35%的GBA1L444P突变增加了认知风险 PD下降了5倍。我们发现，携带GBA1L444P杂合子的小鼠在 海马体功能的行为任务，以及海马区突触标志物的减少，但不包括其他 大脑区域。此外，GBA1L444P杂合子小鼠注射预先形成的α-突触核蛋白纤维诱导 内源性α-突触核蛋白形成的包涵体，在海马区显示更丰富的包涵体 与野生型小鼠相比。此外，我们和其他人发现，脂类、葡萄糖鞘氨醇而不是 在GBA1L444P杂合子小鼠中，葡萄糖神经酰胺增加，提示这种脂质导致了病理和 应成为PD-GBA1治疗的靶点。GlcSph升高和α-SYN增强的联合影响 海马区的聚集可能是LBDS患者认知受损的一种机制，这将是 在本提案中进行了探讨。首先，我们将确定脑组织中葡萄糖鞘氨醇是否升高。 患有PD-GBA1的个体和对照组。我们还将利用人类α-突触核蛋白聚集的模型来 确定病理性α-突触核蛋白是否导致海马神经鞘糖脂代谢的变化 大脑皮层区域。由于还原的葡萄糖脑苷酶已被证明会损害溶酶体功能，我们 将使用原代海马神经元来确定葡萄糖鞘氨醇是否损害溶酶体活性，导致 异常α-突触核蛋白的积聚。最后，我们将使用独立的方法来减少GBA1中的GlcSph L444P杂合子和野生型小鼠，有和没有α-突触核蛋白病理，以确定是否降低这种 脂质可防止海马体生理和相关行为的缺陷。总体而言，该项目将有助于确定 GBA1L444P促进认知功能下降并帮助确定治疗策略的机制 防止认知症状的发展。

Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB) are two neurodegenerative diseases characterized by cognitive impairments that include executive dysfunction, visual-spatial processing difficulties and impaired working memory. Cognitive impairments are among the most debilitating symptoms of these diseases, often leading to institutionalization and severe decline in health. In PD, cognitive symptoms are often present at diagnosis, but can appear over the course of the disease. In DLB, cognitive changes appear first followed by the development of motor parkinsonism. Both diseases, collectively termed Lewy body dementias, are pathologically characterized by aggregates containing the protein α-synuclein, called Lewy pathology. Lewy pathology is found in brain areas important for cognition including the cortex and hippocampus where it correlates with cognitive decline. Genetic variations in the gene, GBA1, also associate with LBDs. GBA1 encodes for glucocerebrosidase an enzyme that metabolizes glucosylceramide. Mutations in glucocerebrosidase reduce its enzyme activity. Up to 12% of PD cases involved genetic variations in GBA1. The GBA1L444P mutation, which represents about 35% of all PD-GBA1 mutations, increases risk of cognitive decline in PD by 5X. We have found that mice heterozygous for GBA1L444P show impaired performance in behavioral tasks of hippocampal function, and reduced synaptic markers in the hippocampus but not other brain regions. In addition, GBA1L444P heterozygous mice injected with pre-formed α-synuclein fibrils to induce formation of inclusions from endogenous α-synuclein, show more abundant inclusions in the hippocampus compared to wild type mice. In addition, we and others have found that the lipid, glucosylsphingosine but not glucosylceramide is increased in GBA1L444P heterozygous mice, suggesting this lipid causes pathology and should be the target of PD-GBA1 therapies. The combined impact of increased GlcSph and enhanced α-syn aggregation in the hippocampus could be a mechanism by which cognition is impaired in LBDs, which will be explored in this proposal. First, we will determine if glucosylsphingosine is elevated in brain tissue from individuals with PD-GBA1 and controls. We will also utilize a model of human α-synuclein aggregation to determine if pathologic α-synuclein causes changes in glycosphingolipid metabolism in hippocampal and cortical brain regions. Because reduced glucocerebrosidase has been shown to impair lysosome function, we will use primary hippocampal neurons to determine if glucosylsphingosine impairs lysosome activity, leading to a build-up of abnormal α-synuclein. Finally, we will use independent methods to reduce GlcSph in GBA1 L444P heterozygous and wild type mice with and without α-synuclein pathology to determine if decreasing this lipid prevents defects in hippocampal physiology and related behaviors. Overall, this project will help determine mechanisms by which GBA1L444P contributes to cognitive decline and help identify therapeutic strategies to prevent development of cognitive symptoms.