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

摘要 认知障碍是帕金森病（PD）的一个常见但知之甚少的非运动方面， 对患者的功能能力、生活质量和最终寿命产生负面影响。的机制 PD中潜在的认知障碍在很大程度上是不确定的，限制了治疗和预防策略。这 该项目的目的是促进我们的认知的细胞和分子基础的理解， 帕金森病易感基因GBA 1杂合突变相关的损害 (PD)其编码溶酶体水解酶葡糖脑苷脂酶（GCase）。纯合子GBA 1突变 导致戈谢病（GD），最常见的溶酶体储存障碍，而杂合突变， GBA 1的基因型构成了PD最强的遗传危险因素。虽然越来越多的证据表明GBA 1 突变加剧PD中的认知障碍和路易体病理，其机制仍不清楚。 我们的初步结果显示L444 P 突变型GBA 1杂合敲入（GBA 1 L444 P/WT）小鼠模型。GBA 1 L444 P/WT小鼠显示， 海马α-突触核蛋白（αSyn）蓄积和脂质谱改变。根据这些初步调查结果， 我们假设L444 P GBA 1突变通过αSyn干扰突触和认知功能， 积累和/或脂质变化，并且L444 P GBA 1突变与PD相关损伤相互作用，例如， 异常αSyn积累，加速认知能力下降。我们的具体目标是（1）表征预- 和突触后变化，这些变化是GBA 1 L444 P/WT小鼠中海马突触可塑性受损的基础;（2） 鉴定GBA 1 L444 P/WT小鼠中突触和认知障碍的分子和细胞机制; 以及（3）确定GBA 1突变是否加重αSyn病理、神经元损失、突触和突触后神经元损伤， Thy 1-αSyn表现前PD小鼠模型中的认知障碍。成功完成本研究将 不仅提供了对认知障碍的关键过程的机械见解， GBA 1突变，但也提供了有价值的动物模型，用于询问PD中的神经退行性通路 和用于治疗筛选。

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.