A New E3 Ligase Implicated in Protein Quality Control and Neurodegeneration

一种与蛋白质质量控​​制和神经变性有关的新 E3 连接酶

• 批准号: 8787516
• 负责人: CLAUDIO A.P. JOAZEIRO
• 金额: $ 41.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787516
• 关键词: Afferent Neurons; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Basic Science; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Process; Cells; Cellular biology; Defect; Development; Disease; Disease model; Drug Targeting; Eukaryota; Eukaryotic Cell; Exhibits; Gene Expression; Genes; Genetic study; Goals; Homologous Gene; Human; Huntington Disease; In Vitro; Lead; Mammalian Cell; Mammals; Mass Spectrum Analysis; Mediating; Messenger RNA; Modeling; Modification; Molecular; Molecular Chaperones; Molecular Genetics; Motor Neurons; Mus; Mutation; Names; Nerve Degeneration; Neurodegenerative Disorders; Organism; Orthologous Gene; Paralysed; Parkinson Disease; Pathogenesis; Pathway interactions; Poly(A) Tail; Prevalence; Process; Production; Proteins; Public Health; Quality Control; Reaction; Regulation; Reporting; Research; Research Design; Research Proposals; Ribosomes; Role; Saccharomycetales; Signal Transduction; Specific qualifier value; System; Terminator Codon; Testing; Therapeutic Intervention; Tissues; To specify; Translations; Ubiquitin; Ubiquitination; Work; Yeasts; base; early onset; gene discovery; gene function; mRNA Decay; mouse model; novel; novel therapeutics; polypeptide; protein aggregate; protein aggregation; protein degradation; reconstitution; tissue culture; ubiquitin-protein ligase; yeast genetics

7. PROJECT SUMMARY Background and relevance: The goal of this basic research proposal is to better understand the causes of neurodegenerative disorders at the molecular level. Among the best known examples are Alzheimer's, Parkinson's and Huntington's diseases, and Amyotrophic Lateral Sclerosis (ALS). Neurodegenerative diseases are incurable and debilitating conditions with increasing prevalence, and without their pathogenic mechanisms being elucidated in sufficient detail, our ability to generate a rationale for corrective therapeutic interventions is greatly limited. We had previously characterized a novel mouse model of neurodegeneration caused by mutation of the LISTER gene. Consistent with an important biological function, this gene is conserved in all organisms from yeast to humans. Accordingly, we have been utilizing various models to discover the gene function and how defects in this function may lead to the disease. The LISTER gene encodes a protein that acts as an E3 ubiquitin ligase, named Listerin. More recently, using yeast we discovered a function for Listerin that is consistent with a role in neurodegeneration in mammals: it functions in a process known as protein quality control whereby aberrant proteins are targeted for degradation. Specifically, its targets are proteins encoded by defective mRNA lacking stop codons ("non-stop proteins"). Listerin functions by tagging those aberrant proteins with molecules of ubiquitin (ubiquitination), which often acts as a destruction signal. Mutation of Listerin causes those toxic proteins to accumulate. With the proposed research we plan to specify the features of Listerin-mediated ubiquitination and expand the findings towards disease. Objective/Hypothesis: Our main hypotheses are that (a) Listerin acts in protein quality control by ubiquitinating non-stop polypeptides stalled in ribosomes, and (b) defective Listerin-mediated degradation leads to the formation of protein aggregates and inclusions, which are hallmarks of neurodegeneration. The Specific Aims are to characterize Listerin's function in non-stop protein degradation, to investigate the extent of conservation of Listerin's function in protein quality control, and to investigate how defects in this function lead to neurodegeneration. Our long-term objective is to help elucidate molecular mechanisms involved in the pathogenesis of human neurodegenerative disease. Study design: We will use biochemistry and yeast molecular genetics to specify how the E3 recognizes its specific target substrates; mammalian tissue culture and biochemistry to investigate the regulation of non-stop protein degradation by mammalian Listerin and biochemistry and cell biology to study the consequences of non-stop protein accumulation in cells.

7. 项目总结