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

葡萄糖脑苷脂酶（GBA1）突变相关认知障碍的细胞和分子基础

基本信息

批准号：
10227055
负责人：
Guomei Tang
金额：
$ 35.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227055
关键词：
AMPA Receptors Activities of Daily Living Acute Age of Onset Animal Model Brain Disease Dopamine Drug Targeting Dyes Error Sources Exhibits Frequencies Gaucher Disease Hippocampus (Brain)Human Hydrolase Idiopathic Parkinson Disease Impaired cognition Impairment Kinetics Knock-in Knock-in Mouse Knock-out Lewy body pathology Lipids Long-Term Potentiation Longevity Lysosomes Mediating Membrane Microdomains Memory impairment Microscopic Molecular Morphology Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurobehavioral Manifestations Neurons Parkinson Disease Pathology Pathway interactions Patients Physiologic pulse Physiological Prevention strategy Process Proteins Quality of life Severities Site Slice Structure Susceptibility Gene Synapses Synaptic Transmission Synaptic plasticity Synaptosomes Therapeutic Transgenes Vesicle Western Blotting Wild Type Mouse alpha synuclein base cognitive function cognitive impairment in Parkinson&apos s design effective therapy genetic risk factor glucosylceramidase insight lipidomics mouse model mouse synuclein alpha mutant mutation carrier negative affect neuron loss new therapeutic target overexpression postsynaptic presynaptic promoter screening synaptic function transmission process treatment strategy

项目摘要

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.

抽象的认知障碍是帕金森病 (PD) 的一个常见但人们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。 PD 潜在的认知障碍在很大程度上尚不明确，这限制了治疗和预防策略。该项目旨在增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 杂合突变相关的损伤 (PD) 编码溶酶体水解酶葡萄糖脑苷酶 (GCase) 纯合 GBA1 突变。引起戈谢病（GD），这是最常见的溶酶体贮积症，而杂合突变 GBA1 构成 PD 最强的遗传风险因素，而越来越多的证据表明 GBA1 是 PD 的最强遗传风险因素。突变会加重帕金森病的认知障碍和路易体病理，但其机制仍不清楚。我们的初步结果显示 L444P 的海马突触可塑性受损和认知功能障碍 GBA1L444P/WT 小鼠模型显示突变型 GBA1 杂合敲入 (GBA1L444P/WT) 小鼠。海马 α-突触核蛋白 (αSyn) 的积累和脂质分布的改变基于这些初步发现，我们发现 L444P GBA1 突变通过 αSyn 破坏突触和认知功能累积和/或脂质变化，并且 L444P GBA1 突变与 PD 相关损伤相互作用，例如，异常的αSyn积累，加速认知能力下降，我们的具体目标是（1）表征预- GBA1L444P/WT 小鼠海马突触可塑性受损的突触后变化 (2) 确定 GBA1L444P/WT 小鼠突触和认知障碍的分子和细胞机制； (3) 确定 GBA1 突变是否会恶化 αSyn 病理学、神经元损失、突触和 Thy1-αSyn 预表现 PD 小鼠模型中的认知障碍将成功完成本研究。不仅提供了对由认知障碍引起的认知障碍的关键过程的机械见解 GBA1 突变，而且还提供有价值的动物模型来研究 PD 的神经退行性通路以及用于治疗筛选。