Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases

1R01AG074609-01 张虎有限公司 在包括阿尔茨海默病(AD)在内的大多数神经退行性疾病中，一种或多种蛋白质在疾病进展过程中聚集。在肌萎缩侧索硬化症(ALS)、额颞叶痴呆(FTD)、阿尔茨海默病(AD)和其他AD相关痴呆(ADRD)的病例中，在很大比例的散发性和家族性疾病患者中观察到反式反应DNA结合蛋白43 kDa(TDP-43)的胞浆包涵体。这种胞浆TDP-43的异常积聚被认为是毒性功能获得和核功能丧失的致病机制的基础；因此，阻止这些包涵体的形成或促进这些包涵体的清除可能是治疗TDP-43蛋白病(如AD和ADRDS)的有效途径。目前，还没有有效的疗法来改变大多数与TDP-43蛋白病相关的神经退行性疾病的进程。我们最近发现NEMO样激酶(NLK)是溶酶体的负调节因子，溶酶体是参与细胞蛋白质质量控制的关键细胞器，能够清除有毒的聚集蛋白。本研究旨在更好地了解NLK调节神经系统溶酶体基因表达的基本分子机制，并在ADRD动物模型中验证NLK对TDP-43聚集的调节作用。我们提出了以下三个具体目标。目标1将使用无偏见和有针对性的方法来揭示Nlk对神经元中溶酶体基因表达调控的基本机制见解。目的2利用野生型和TDP-43动物模型，在体内确定NLK在调节溶酶体和TDP-43蛋白病变中的作用。目的3将扩大拟议研究的范围，通过体内成年期不同时间NLK水平的遗传和药理学降低，了解NLK在TDP-43聚集的动物模型中的治疗意义。为此，我们将测试NLK减少在控制ADRD TDP-43小鼠模型的病理和运动行为变化的发生和进展方面的效果。AIMS 2和3将提供关键的原则证据，证明溶酶体调节在蛋白质聚集障碍的临床前模型中的有效性。总之，该项目将揭示参与神经元溶酶体调节的新分子，这些分子可能成为治疗各种神经退行性疾病的潜在靶点，包括AD和几种AD相关疾病。

1R01AG074609-01 Janghoo Lim In the majority of neurodegenerative diseases, including Alzheimer’s disease (AD), one or more proteins aggregate over the course of disease progression. In the case of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), AD, and other AD-related dementias (ADRDs), cytoplasmic inclusions of transactive response DNA binding protein 43 kDa (TDP-43) are observed in a large percentage of patients with sporadic and familial forms of disease. This aberrant accumulation of cytoplasmic TDP-43 is thought to underlie gain of toxic functions and exacerbate loss of nuclear function pathogenic mechanisms; therefore, preventing the formation or promoting the clearance of these inclusions may be an effective therapeutic approach for TDP-43 proteinopathies, such as AD and ADRDs. Currently, there are no therapeutics that effectively alter the course of most neurodegenerative diseases associated with TDP-43 proteinopathy. We have recently identified Nemo-like kinase (Nlk) as a negative regulator of the lysosome, a key organelle involved in cellular protein quality control that is capable of clearing toxic aggregated proteins. This proposal aims to better understand the basic molecular mechanism of Nlk’s regulation of lysosome gene expression in the nervous system and to test the modulatory effects of Nlk in ADRD animal models of TDP-43 aggregation. We propose the following three specific aims. Aim 1 will employ unbiased and targeted approaches to uncover fundamental mechanistic insights into the regulation of lysosome gene expression by Nlk in neurons. Aim 2 will determine which cell types mediate the function of Nlk in the regulation of the lysosome and TDP-43 proteinopathy in the nervous system in vivo using wild-type and TDP-43 animal models. Aim 3 will expand the scope of the proposed study to understand the therapeutic implications of Nlk reduction in animal models of TDP-43 aggregation through genetic and pharmacological reduction of Nlk levels at varying times in adulthood in vivo. In doing so, we will test the effect of Nlk reduction in the control of the onset and progression of pathological and motor behavioral changes in TDP-43 mouse models of ADRD. Aims 2 and 3 will provide critical proof-of-principle evidence regarding the effectiveness of lysosomal modulation in pre-clinical models of protein aggregation disorders. Together, this project will reveal novel molecules involved in lysosomal regulation in neurons that may be potential targets in the treatment of various neurodegenerative diseases, including AD and several AD-related disorders.