Investigation of UBQLN2 in neuronal dysfunction and ALS-FTD

UBQLN2 在神经元功能障碍和 ALS-FTD 中的研究

基本信息

批准号：
10638277
负责人：
Alexandra Whiteley
金额：
$ 57.22万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638277
关键词：
ALS patients Affect American Animal Model Animals Axon Binding Binding Proteins Biology Brain Cell Nucleus Cell model Cells Client Complement Cytosol Data Defect Development Diagnosis Disease Disease Pathway Disease model Family Functional disorder Future Gene Expression Gene Expression Regulation Generations Genes Genetic Genetic Transcription Genome Goals Histologic Human Hydrophobicity Impaired cognition In Vitro Inheritance Patterns Investigation Laboratories Lead Link Longevity Mediating Modeling Molecular Motor Neurons Mus Mutation Names Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nucleic Acid Binding Nucleocapsid Pathway interactions Patients Peptide Hydrolases Phenotype Placentation Process Protease Domain Protein Fragment Proteins Proteome Proteomics Publishing Research Research Personnel Rest Retrotransposon Retroviridae Retrovirus Proteins Role Spinal Cord Structure Symptoms Synapses Therapeutic Tissues Up-Regulation Viral Virus Work Zinc Fingers brain tissue disease phenotype drug development effective therapy familial amyotrophic lateral sclerosis fighting frontal lobe frontotemporal lobar dementia amyotrophic lateral sclerosis in vivo misfolded protein molecular modeling motor impairment multicatalytic endopeptidase complex novel nucleic acid binding protein programs protein degradation sporadic amyotrophic lateral sclerosis ubiquilin

项目摘要

Amyotrophic Lateral Sclerosis with frontotemporal dementia (ALS-FTD) is a progressive, fatal neurodegenerative disease that results from the loss of upper and lower motor neurons, as well as neurons of the frontal cortex. The resulting symptoms of ALS-FTD are progressive motor and cognitive impairment. Little is known about the underlying mechanism of disease, and there are no effective treatments that significantly lengthen lifespan. 10% of ALS-FTD cases show a familial pattern of inheritance and can often be traced to mutation of specific genes. Familial ALS-FTD (fALS-FTD) shares key features with sporadic ALS-FTD, meaning that the study of fALS-FTD can provide broadly applicable findings in the fight against this devastating disease. Mutations in the human UBQLN2 gene lead to a portion of fALS-FTD cases, but the mechanism of disease is poorly understood. UBQLNs are a family of proteasome shuttle factors which facilitate proteasomal degradation of ‘difficult’ proteasome substrates, though the identity of these substrates has been elusive. We recently published that UBQLN2 regulates proteasomal degradation of the protein PEG10. PEG10, or ‘paternally expressed gene 10’, is a ‘domesticated retrotransposon’: it resembles retrotransposons and retroviruses in its overall structure, but is unable to transpose within the genome. Like its viral cousins, the PEG10 protein contains a nucleic-acid binding zinc finger and a protease domain, both with unknown function. We recently discovered that PEG10 is an active self-protease and releases a protein fragment containing the nucleic acid-binding region which then traffics to the nucleus. Expression of this fragment alone is sufficient to upregulate expression of genes involved in axon remodeling, which are similarly upregulated in ALS-FTD tissues. Therefore, PEG10 is an excellent candidate for the molecular cause of ALS-FTD upon UBQLN2 dysfunction. In our model, UBQLN2 loss or dysfunction leads to PEG10 accumulation, increased liberation of the nucleic acid-binding fragment, and upregulated axon remodeling genes, leading to phenotypes of disease. This proposal seeks to validate and explore our new model of disease in depth with a complement of in vitro and in vivo approaches. Our goals for the next five years are to generate a deep understanding of the UBQLN2-PEG10 relationship and how it influences the development of ALS-FTD. In our first Aim, we carefully examine the abundance and proteolytic activity of PEG10 in ALS and FTD patient tissue. In our second Aim, we determine the mechanism and precise contribution of PEG10 in cellular and animal models of UBQLN2-mediated disease. Finally, we dive deeply into the molecular underpinnings of UBQLN2-PEG10 interactions in order to generate the first detailed model for UBQLN client selection. The findings from our research program will transform our basic understanding of PEG10 function as well as UBQLN2 biology, and may provide crucial new targets for the fight against ALS-FTD.

肌萎缩性侧索硬化症患有额颞痴呆（ALS-FTD）是一种渐进的致命性神经退行性疾病是由于上下运动神经元丧失以及神经元的神经元引起的额叶皮层。 ALS-FTD的结果符号是渐进的运动和认知障碍。几乎没有关于疾病的潜在机制已知，并且没有有效的治疗方法显着延长寿命。 10％的ALS-FTD案件显示出家族的继承模式，通常可以追溯到特定基因的突变。家族性ALS-FTD（fals-ftd）与零星的ALS-FTD共享关键特征，含义对FALS-FTD的研究可以在与这种毁灭性疾病的斗争中提供广泛适用的发现。人ubqln2基因中的突变导致一部分fals-ftd病例，但是疾病知之甚少。 UBQLN是促进蛋白酶体的蛋白酶体班车因子系列尽管这些底物的身份难以捉摸，但“困难”蛋白酶体底物的降解。我们最近发布的UBQLN2调节蛋白质PEG10的蛋白酶体降解。 PEG10，或'paternally 表达的基因10'，是“驯化的逆转座子”：它类似于逆转录病毒和逆转录病毒总体结构，但无法在基因组中转介。像其病毒堂兄一样，PEG10蛋白包含核酸结合锌指和蛋白质结构域，均具有未知功能。我们最近发现 PEG10是一种活跃的自我捕食，并释放包含核酸结合区域的蛋白质片段然后流动到核。仅此片段的表达就足以更新参与轴突重塑的基因，在ALS-FTD组织中类似地更新。因此，PEG10是 UBQLN2功能障碍后ALS-FTD的分子原因的出色候选者。在我们的模型中，ubqln2 损失或功能障碍会导致PEG10的积累，核酸结合片段的释放增加，并且轴突重塑基因上调，导致疾病表型。该建议旨在验证和通过完成体外和体内方法，深入探索我们的新疾病模型。我们接下来五年的目标是对UBQLN2-PEG10产生深刻的了解关系及其如何影响ALS-FTD的发展。在我们的第一个目标中，我们仔细检查了 PEG10在ALS和FTD患者组织中的抽象和蛋白水解活性。在我们的第二个目标中，我们确定 PEG10在UBQLN2介导的疾病的细胞和动物模型中的机制和精度贡献。最后，我们深入研究UBQLN2-PEG10相互作用的分子基础 UBQLN客户端选择的第一个详细模型。我们的研究计划的发现将改变我们的对PEG10功能以及UBQLN2生物学的基本了解，并可能为该功能提供至关重要的新目标与ALS-FTD作斗争。