权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of a GBA p.E326K associated Parkinsons disease and Dementia with Lewy body mouse model

GBA p.E326K 相关帕金森病和痴呆症路易体小鼠模型的开发

基本信息

批准号：
10011905
负责人：
LORRAINE N CLARK
金额：
$ 8.1万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011905
关键词：
Affect Age of Onset Alleles Animals Biochemical Bradykinesia Brain Ceramide glucosyltransferase Ceramides Clinical Clinical Trials Defect Development Disease Enzymes Functional disorder Future Gaucher Disease Generations Genes Genetic Models Glucose Glucosylceramides Goals Human Impaired cognition Knock-in Mouse Lead Lewy Body Dementia Lewy body pathology Link Lysosomes Metabolism Molecular Chaperones Motor Mus Mutation Neurodegenerative Disorders Neurologic Neurologic Symptoms Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathology Pathway interactions Penetrance Phenotype Play Point Mutation Proteins Residual state Rest Tremor Risk Risk Factors Role Severity of illness Sphingosine Therapeutic Therapeutic Uses Transgenes Transgenic Organisms Variant alpha synuclein behavioral phenotyping cognitive function disease phenotype endoplasmic reticulum stress enzyme activity glucosylceramidase glucosylsphingosine inhibitor/antagonist loss of function macrophage mouse model mutant neuropathology non-motor symptom overexpression targeted treatment therapeutic development

项目摘要

Gaucher disease (GD), one of the most common autosomal recessive lysosomal storage disorders, is caused by mutations in the Glucocerebrosidase (GBA) gene. The enzyme encoded by GBA, Gcase1, catalyzes the conversion of glucosylceramide (GlcCer) to glucose and ceramide. The primary defect in GD is the accumulation of GlcCer in lysosomes and is seen most prominently in macrophages. We and others have shown that specific mutations in the GBA gene, in the heterozygous state, are a risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Functional studies have demonstrated an interaction between α-synuclein and GBA protein and mutant GBA proteins can cause an increase in α-synuclein (SNCA) levels and lysosomal dysfunction. Among the GBA variants associated with PD, p.E326K is one of the most frequent. Interestingly, the GBA p.E326K variant is only involved in GD when it is found in the same allele (in cis) with other ‘severe’ type mutations (e.g. p.L444P) and contributes to GD severity by further reducing residual enzyme activity. Although biochemical observations have suggested that p.E326K is a ‘mild’ type loss of function variant, this reduction in activity is clearly not severe enough to lead to a GD phenotype. Understanding the mechanistic links between specific GBA mutations and PD is critical for developing targeted therapeutic approaches. Currently, it is unclear how the GBA p.E326K mutation contributes to a neurological phenotype and pathology in the brain. More recent studies suggest that ceramide metabolism and its metabolites play a central role in disease pathogenesis of GBA-associated PD and DLB. We hypothesize that the GBA p.E326K variant, contributes to disease by a mechanism involving an imbalance (increase) of other metabolites in the ceramide metabolism pathway namely Glucosylsphingosine (GlcSph) and Sphingosine (Sph) leading to α-synuclein aggregation and ER stress. Currently, therapeutic approaches to treat GBA associated PD are limited to a glucosylceramide synthase inhibitor and a molecular chaperone, ambroxol hydrochloride, both of which are currently in clinical trials. Development of a mouse model for the most common GBA variant associated with PD, the GBA p.E326K variant, and determining the disease mechanism may open up new avenues for therapeutic development targeting ASAH1 or GBA2 in the ceramide pathway and could have a major impact on the field. The goal of this proposal is to develop and characterize a Gba p.E326K mouse model that can be used for therapeutic development in future studies. we propose two specific aims. Specific Aim 1 is to generate and characterize a Gba p.E326K mouse model of PD and DLB and Specific Aim 2 is to determine whether overexpression of the human A30P α-synuclein (SNCA) transgene modifies penetrance in Gba p.E326K mice and affects age of onset and progression of neurological symptoms.

戈谢病（GD）是最常见的常染色体隐性溶酶体贮积性疾病之一