Gene Deregulation in Cortical Dementia

额颞叶痴呆(FTD)是一种常见的与衰老相关的神经退行性疾病，具有广泛的共性 肌萎缩侧索硬化症(ALS)的临床、病理和遗传特征。最新进展 遗传学研究表明，大多数ALS基因的致病突变也是导致FTD的原因。相当可观 遗传学研究的证据表明，Ubqln2是ALS和FTD的致病基因，但Ubqln2是如何 导致这种疾病的原因尚不清楚。Ubqln2的过表达及其致病突变引起 难以区分的表型使人想起ALS和FTD，表明致病突变或过度 Ubqln2的表达在两种疾病中均有致病作用。就像基因敲除啮齿动物中Ubqln2的缺失一样 致病基因Ubqln2不影响神经功能，可能通过未知功能的获得而导致疾病。 Ubqln2相关疾病的一个显著特征是蛋白质聚集，这种聚集在转基因中复制得很好。 啮齿动物过度表达Ubqln2。利用生化方法，我们试图解开Ubqln2的致病机制 通过其获得的易于聚集的特征诱导神经元功能障碍。我们的初步研究发现， 在FTD患者和miRNA缺乏症患者中，Ubqln2被解除调节。这项拟议的研究将决定如何 新型大鼠模型中Ubqln2表达下调与认知功能受损和神经元死亡相关 以及miRNA缺乏如何导致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Ubqln2相关疾病的机械洞察，并可能 将确定一个对神经元生存和认知功能至关重要的基因网络。

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.