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Protein Arginine Deiminase 2 (PAD2) and Protein Citrullination in ALS

ALS 中的蛋白质精氨酸脱亚胺酶 2 (PAD2) 和蛋白质瓜氨酸化

基本信息

批准号：
10298171
负责人：
ZUOSHANG XU
金额：
$ 48.77万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298171
关键词：
Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Area Astrocytes Atherosclerosis Calcium Cell physiology Cessation of life Charge Citrulline Cytoskeleton DNA Sequence Alteration Dimensions Disease Disease Progression Gene Expression Human Immune Response Genes Impairment Inflammation Inflammatory Investigation Isoenzymes Knowledge Lead Lupus Malignant Neoplasms Mammals Membrane Modeling Modification Multiple Sclerosis Mus Muscle Weakness Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Nucleic Acids Paralysed Parkinson Disease Pathogenesis Pathologic Post-Translational Protein Processing Prion Diseases Protein-arginine deiminase Proteins Proteomics Public Health RNA Processing Reaction Reactive Oxygen Species Research Role Signal Transduction Site Spinal Cord Substrate Specificity Tissues Toxic effect amyotrophic lateral sclerosis therapy cell type central nervous system injury citrullinated protein early detection biomarkers endoplasmic reticulum stress inhibitor/antagonist link protein mitochondrial dysfunction motor disorder motor neuron degeneration mouse model mutant neuroinflammation novel marker novel therapeutics nucleocytoplasmic transport phenomenological models protein aggregation protein function protein structure function targeted treatment

项目摘要

Project Summary Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron degeneration, muscle weakness, paralysis, and death. The mechanism of motor neuron degeneration is incompletely understood, and currently, no therapy can arrest or reverse the disease progression. To understand the disease and open new avenues for therapy, exploring new mechanisms of the disease is needed. To this end, the Xu and Thompson labs have joined forces to investigate the role of protein citrullination, which is catalyzed by Protein Arginine Deiminases (PADs), in ALS. Citrullination removes positive charges from proteins. Therefore, this modification can alter the protein function and its interaction with other proteins, membranes, and nucleic acids. Mammals have five PADs: PADs 1–4 and PAD6. PAD2 is the dominant form in the central nervous system (CNS). Previous studies have shown that PAD2 and protein citrullination are increased in neurodegenerative diseases such as Alzheimer's disease and Prion disease. However, no studies have linked PADs and protein citrullination with ALS. Furthermore, no studies have investigated the functional role of PAD2 and protein citrullination in neurodegeneration. To fill these knowledge gaps, the Xu and Thompson labs have applied their combined expertise in ALS and protein citrullination and initiated this investigation. Our preliminary studies show unequivocal evidence that PAD2 expression (but not PAD3, 4) and protein citrullination are spatially and temporally altered in two ALS mouse models, one expressing mutant SOD1G93A and the other expressing mutant PFN1C71G. While PAD2 expression is increased in astrocytes, its expression is decreased in neurons during the disease progression. By proteomics, we identified several hundred citrullinated proteins in the spinal cord. In ALS mice, the early disease stage is dominated by decreased protein citrullination. In contrast, the late disease stage shows increased citrullination in one-half of the proteins and decreased citrullination in the other half. Intriguingly, the highly citrullinated proteins are enriched in the insoluble fractions in the late stage. We propose to further our investigation by answering the following seven questions: (1) How is protein citrullination altered in ALS? (2) What are the citrullinated proteins in the spinal cord, and how is citrullination altered in these proteins in ALS? (3) What are the sites of citrullination on ALS-associated proteins? (4) Is PAD2 responsible for the altered protein citrullination in ALS? (5) How does protein citrullination impact protein aggregation? (6) How does the citrullination of ALS-associated targets impact their protein function? (7) How is protein citrullination altered in human ALS? By answering these questions, we will enter and investigate a hitherto unexplored research area in ALS, thereby opening a new dimension in understanding the mechanism of neurodegeneration in ALS. Because PAD inhibitors have already been developed in the Thompson lab, this new dimension may lead to new therapeutic avenues targeting PAD2 activity. Because of the significant changes in protein citrullination, this research may also identify novel biomarkers of early-stage ALS. 1

项目总结