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Gene Deregulation in Cortical Dementia

皮质痴呆的基因失调

基本信息

批准号：
10191132
负责人：
xugang xia
金额：
$ 353.16万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10191132
关键词：
Gene Deregulation Cortical Dementia

项目摘要

Frontotemporal dementia (FTD) is a common aging-related neurodegenerative disease and shares a wide spectrum of clinical, pathological, and genetic features with amyotrophic lateral sclerosis (ALS). Recent advance in genetics study indicates that pathogenic mutations of most ALS genes are also causative to FTD. Substantial evidence from genetics study suggests Ubqln2 as a causative gene of both ALS and FTD, but how Ubqln2 causes the diseases is not known. Overexpression of Ubqln2 with or without a pathogenic mutation causes indistinguishable phenotypes reminiscent of ALS and FTD, suggesting that pathogenic mutation or excess expression of Ubqln2 is both pathogenic for the diseases. As deletion of the Ubqln2 in knockout rodents does not affect neuronal function, pathogenic Ubqln2 likely causes the diseases through a gain of unknown function. A prominent feature of Ubqln2 related diseases is protein aggregation, which is well reproduced in transgenic rodents overexpressing Ubqln2. Using biochemical approaches, we attempt to unravel how pathogenic Ubqln2 induces neuronal dysfunction via its gained aggregation-prone feature. Our preliminary studies observed that Ubqln2 is deregulated in FTD patients and at miRNA deficiency. The proposed research will determine how deregulated Ubqln2 expression is related to impaired cognitive function and neuronal death in novel rat models and how miRNA deficiency leads to deregulated Ubqln2 expression and to cortical dementia in the diseases. Upon completion, the proposed research will gain a mechanistic insight on Ubqln2 related diseases and likely will identify a network of genes essential to neuronal survival and cognitive function.

额颞叶痴呆（Frontotemporal dementia，FTD）是一种常见的与衰老相关的神经退行性疾病，肌萎缩侧索硬化症（ALS）的临床、病理和遗传特征谱。研究进展遗传学研究表明，大多数ALS基因的致病性突变也是FTD的病因。实质性来自遗传学研究的证据表明Ubqln2是ALS和FTD的致病基因，但Ubqln2如何引起疾病的原因尚不清楚。Ubqln2的过表达（有或没有致病性突变）会导致难以区分的表型使人联想到ALS和FTD，这表明致病性突变或过量 Ubqln 2的表达对于这些疾病都是致病的。由于敲除啮齿动物中Ubqln 2的缺失致病性Ubqln 2可能通过获得未知的功能而引起疾病。 Ubqln2相关疾病的一个突出特征是蛋白质聚集，其在转基因小鼠中很好地再现。过表达Ubqln 2的啮齿类动物。使用生物化学方法，我们试图解开致病性Ubqln 2 通过其获得的聚集倾向特征诱导神经元功能障碍。我们的初步研究发现， Ubqln2在FTD患者和miRNA缺乏时失调。这项研究将确定如何 Ubqln2表达失调与新型大鼠模型中认知功能受损和神经元死亡相关以及miRNA缺陷如何导致Ubqln2表达失调和疾病中的皮质痴呆。完成后，拟议的研究将获得对Ubqln 2相关疾病的机制见解，将确定神经元存活和认知功能所必需的基因网络。