Cellular and Molecular basis for cognitive impairment associated with Glucocerebrosidase (GBA1) mutation

摘要 认知障碍是帕金森氏病(PD)常见但知之甚少的非运动方面，它 对患者的功能能力、生活质量和最终寿命产生负面影响。其作用机制 帕金森病潜在的认知损害在很大程度上是未知的，限制了治疗和预防策略。这 该项目旨在促进我们对认知的细胞和分子基础的理解 与帕金森病易感基因GBA1杂合突变相关的损害 (Pd)编码溶酶体水解酶葡萄糖脑苷酶(GCase)。GBA1纯合子突变 导致高谢病(GD)，这是最常见的溶酶体储存障碍，而杂合突变 GBA1是帕金森病最强的遗传危险因素。虽然越来越多的证据表明GBA1 突变可加重帕金森病患者的认知障碍和路易体病理，其机制尚不清楚。 我们的初步结果显示L444P的海马区突触可塑性受损和认知功能障碍。 突变的GBA1杂合子敲门(GBA1L444P/WT)小鼠模型。GBA1L444P/WT小鼠表现出 海马区α-突触核蛋白(α-Syn)的蓄积和脂谱的改变。根据这些初步调查结果， 我们推测L444PGBA1突变通过α突触干扰突触和认知功能 蓄积和/或脂质改变，以及L444P GBA1突变与帕金森病相关的侮辱相互作用，例如， α蛋白异常堆积，加速认知功能衰退。我们的具体目标是(1)描述Pre-Pre 以及GBA1L444P/WT小鼠海马突触可塑性受损的突触后变化；(2) 探讨GBA1L444P/WT小鼠突触和认知损害的分子和细胞机制； 以及(3)确定GBA1突变是否加剧了αSYN的病理、神经元丢失、突触和 Thy1-αSyn预显性帕金森病小鼠模型中的认知损害。成功完成这项研究将 不仅提供了对导致认知障碍的关键过程的机械性见解， GBA1突变，但也提供了有价值的动物模型来询问帕金森病的神经退变途径 并用于治疗性筛查。

ABSTRACT Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson's disease (PD), which negatively affects patient's functional capacity, quality of life and ultimately lifespan. The mechanisms underlying cognitive impairment in PD are largely undefined, limiting treatment and prevention strategies. This project is designed to advance our understanding of the cellular and molecular basis of the cognitive impairment associated with heterozygous mutations in GBA1, a susceptibility gene for Parkinson's disease (PD) that encodes for the lysosome hydrolase glucocerebrosidase (GCase). Homozygous GBA1 mutations cause Gaucher disease(GD), the most common lysosome storage disorder, whereas heterozygous mutations of GBA1 constitute the strongest genetic risk factor for PD. While accumulating evidence suggests that GBA1 mutations exacerbate cognitive impairment and Lewy body pathology in PD, the mechanisms remain unknown. Our preliminary results revealed impaired hippocampal synaptic plasticity and cognitive dysfunction in a L444P mutant GBA1 heterozygous knockin (GBA1L444P/WT) mouse model. The GBA1L444P/WT mice showed hippocampal accumulation of α-synuclein (αSyn) and altered lipid profiles. Based on these preliminary findings, we hypothesize that the L444P GBA1 mutation disrupts synaptic and cognitive function through αSyn accumulation and/or lipid changes, and that the L444P GBA1 mutation interacts with PD related insults, e.g., abnormal αSyn accumulation, to accelerate cognitive decline. Our specific aims are (1) to characterize pre- and post-synaptic changes that underlie impaired hippocampal synaptic plasticity in the GBA1L444P/WT mice; (2) to identify molecular and cellular mechanisms of synaptic and cognitive impairment in the GBA1L444P/WT mice; and (3) to determine whether the GBA1 mutation exacerbates αSyn pathology, neuronal loss, synaptic and cognitive impairment in a Thy1-αSyn pre-manifest PD mouse model. Successful completion of this study will not only provide mechanistic insights into the key processes that underlie cognitive impairment caused by GBA1 mutations, but also deliver valuable animal models for interrogating neurodegenerative pathways in PD and for therapeutic screening.