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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.

肌萎缩侧索硬化症合并额颞叶痴呆（ALS-FTD）是一种进行性、致命性疾病