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：
10462591
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462591
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氏病（PD）的常见但知之甚少的，这是一个常见的障碍，该方面是普遍的。负面影响患者的功能能力，生活质量和最终寿命。机制 PD中的潜在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。这项目旨在促进我们对认知细胞和分子基础的理解与GBA1中的杂合突变相关的损伤，GBA1是帕金森氏病的易感基因（PD）编码为溶酶体水解酶葡萄糖脑苷酶（GCASE）编码。纯合GBA1突变导致高雪病（GD），最常见的溶酶体储存障碍，而杂合突变 GBA1的构成PD的强遗传危险因素。同时积累证据表明GBA1 突变加剧了PD中的认知障碍和Lewy身体病理，这些机制仍然未知。我们的初步结果表明，L444p的海马突触可塑性和认知功能障碍受损突变的GBA1杂合敲击素（GBA1L444P/WT）小鼠模型。显示的GBA1L444P/WT小鼠 α-突触核蛋白（αSyn）和脂质谱改变的海马积累。基于这些初步发现，我们假设L444P GBA1突变通过αSyn破坏合成和认知功能积累和/或脂质变化，L444p GBA1突变与PD相关侮辱相互作用，例如异常的αSyn积累，以加速认知能力下降。我们的具体目的是（1）表征和突触后的变化是GBA1L444P/WT小鼠中海马突触可塑性受损的基础；（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突变是否加剧了αSyn病理，神经元丧失，突触和 THY1-αSyn前PD小鼠模型中的认知障碍。这项研究成功完成将不仅提供了对认知障碍造成的关键过程的机械见解 GBA1突变，但也提供有价值的动物模型，以询问PD中的神经退行性途径并进行治疗筛查。