Nascent SOD1 in Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症中的新生 SOD1

• 批准号: 7791079
• 负责人: Peter JOHN HART
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791079
• 关键词: 3-Dimensional; Address; Adopted; Affect; Affinity; Age; Aging-Related Process; Amino Acid Substitution; Amino Acids; Amyotrophic Lateral Sclerosis; Antioxidants; Behavior; Binding; Binding Sites; Biochemistry; Cessation of life; Child; Complex; Consultations; Copper; Cultured Cells; DNA Sequence Rearrangement; Data; Defect; Degenerative Disorder; Dimensions; Disease; Dissociation; Disulfides; Enzymes; Event; Exercise; Failure; Familial Amyotrophic Lateral Sclerosis; Family; Future; Gel Chromatography; Generations; Genes; Health Sciences; Hospitals; Human; Inherited; Ions; Iraq; Laboratories; Lead; Lesion; Letters; Light; Link; Measurement; Mediating; Metalloproteins; Metals; Methods; Military Personnel; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Motion; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Neurodegenerative Disorders; Neurons; Paralysed; Parents; Pathway interactions; Patients; Population; Post-Translational Protein Processing; Process; Proline; Proteins; Relative (related person); Reporting; Resolution; SOD1 gene; Sampling; Site; Solutions; Spinal Cord; Structure; Study Section; Temperature; Testing; Texas; Therapeutic; Therapeutic Agents; Time; Toxic effect; Transgenic Mice; Translating; United States; Universities; Variant; Veterans; War; Work; X ray diffraction analysis; X-Ray Crystallography; X-Ray Diffraction; analytical ultracentrifugation; base; cofactor; conformer; copper zinc superoxide dismutase; design; disease-causing mutation; disulfide bond; gain of function; gel electrophoresis; human tissue; in vivo; interest; melting; molecular mass; mouse model; mutant; oxidation; polypeptide; protein aggregation; protein misfolding; public health relevance; relating to nervous system; research study; sedimentation equilibrium; sedimentation velocity; tool

DESCRIPTION (provided by applicant): Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease, motor neuron disease). With increasing age, insoluble forms of mutant SOD1 progressively accumulate in neural tissues of human ALS patients and in spinal cords of transgenic mice expressing these polypeptides, suggesting that SOD1- linked ALS is a protein misfolding and aggregation disorder. Understanding the molecular basis for how the pathogenic mutations give rise to SOD1 folding intermediates that are prone to aggregation is therefore of keen interest. A critical step on the folding pathway occurs when the nascent SOD1 polypeptide is posttranslationally modified by the copper chaperone for SOD1 (CCS), a helper protein that inserts the catalytic copper cofactor and oxidizes the SOD1 intrasubunit disulfide bond. CCS recognizes and binds to nascent, but not mature SOD1, suggesting that the newly translated form exists in a conformation distinct from the mature form. Recent studies reveal that pathogenic SOD1 proteins coming from aggregates isolated from cultured cells and from the spinal cords of transgenic mice tend to be metal-deficient and/or lacking the disulfide bond. These observations suggest the hypothesis that the disease-causing mutations may enhance levels of SOD1 folding intermediates by hindering CCS-mediated SOD1 maturation. The experiments outlined in this project are designed to probe the structure and dynamics of nascent SOD1 and to examine its interaction with CCS. Successful completion of the Aims contained herein will address the following questions: 1) What are the structural determinants that are responsible for the recognition of nascent SOD1 by CCS? 2) Is the functional SOD1/CCS complex heterodimeric, heterotetrameric, or some other higher order oligomer? 3) What are the structural details of the nascent SOD1/CCS complex in three dimensions? 4) What factors govern the interconversion of the nascent and mature SOD1 conformations in the absence of CCS? 5) How do the ALS mutations affect the interconversion of the nascent and mature conformations? Answers to these questions are prerequisites for the design of therapeutic agents aimed inhibiting pathogenic SOD1 aggregation in ALS. 1 PUBLIC HEALTH RELEVANCE: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder linked to the aging process. Military personnel who served in the first U.S.-Iraq war, have developed sporadic (noninherited) ALS upon their return more frequently than found in the United States population as a whole. Familial ALS (fALS) is passed from parent to child over generations, and the underlying genetic defects were entirely unknown until it was discovered that some ALS families possess mutations in the gene encoding the antioxidant enzyme copper- zinc superoxide dismutase (SOD1). Importantly, the manifestations of sporadic and familial ALS are nearly clinically indistinguishable, suggesting that the underlying molecular causes for the two forms of the disease are related. This proposal investigates SOD1-linked ALS because understanding the molecular basis for motor neuron death in familial cases could lead to therapeutic avenues applicable to sporadic forms of the disease, both of which are expected to increasingly affect the veteran population as it continues to age.

描述（由申请人提供）：