Superoxide Dismutase, Peroxynitrite and ALS

超氧化物歧化酶、过氧亚硝酸盐和 ALS

• 批准号: 8269706
• 负责人: JOSEPH S BECKMAN
• 金额: $ 31.34万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269706
• 关键词: Accounting; Active Sites; Address; Affect; Agreement; American; Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Autopsy; Binding; Binding Sites; Brain; Copper; Cu-Superoxide Dismutase; Cuprozinc Superoxide Dismutase; Development; Disease; Disulfides; Dorsal; Environmental Health; Enzymes; Familial Amyotrophic Lateral Sclerosis; Free Radicals; Heart; Horns; Human; In Vitro; Lead; Ligand Binding; Link; Maps; Mass Spectrum Analysis; Measurable; Measures; Metals; Methods; Molecular; Molecular Chaperones; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Nitric Oxide; Onset of illness; Oxidation-Reduction; Paralysed; Patients; Peroxonitrite; Predisposition; Process; Proteins; Rattus; Role; Site; Son; Spatial Distribution; Spinal; Spinal Cord; Staging; Superoxide Dismutase; Superoxides; Testing; Toxic effect; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Tyrosine; Zinc; Zinc deficiency; abstracting; base; copper zinc superoxide dismutase; dimer; disulfide bond; gain of function; in vivo; innovation; killings; mutant; nitration; overexpression; protein aggregation; research study; theories; tool

Abstract ALS is a fatal progressive paralysis affecting 34,000 Americans and killing 8,000 per year. The discovery in 1993 of dominant mutations to Cu,Zn-superoxide dismutase (Cu,Zn- SOD) linked to 2% of ALS cases led to hopes that new treatments for ALS based on antioxidants might be forthcoming. Whereas there is broad agreement that ALS mutant SODs have impaired stability, the specific toxic gain-of-function associated with these mutations is still hotly debated. The two leading explanations are the aggregation hypothesis ¿ that aggregation of mutant SODs is a direct cause of disease ¿ and the zinc-deficient hypothesis ¿ that disease is due to increased redox activity of SOD that has lost zinc but retains copper in its active site. We propose, based on extensive preliminary evidence, that the two hypotheses are intimately interconnected, with aggregation being paradoxically protective by removing zinc-deficient SOD. The zinc-deficient hypothesis also raises the intriguing possibility that SOD could contribute to sporadic ALS. We have innovative mass spectrometric methods to quantitatively measure the metal content of SOD across the spinal cord, which will allow us to critically evaluate the zinc- deficient and aggregation hypotheses and innovatively address the long-standing question as to which aberrant forms of SOD (zinc-deficient or aggregated) occur before disease onset and which accumulate later. Aim 1 will characterize how the dimer interface and the intramolecular disulfide of SOD are affected by ALS-associated mutations, and in turn affect zinc and copper binding as well as propensity for aggregation of SOD. This aim will explore the physical basis underlying metal loss and aggregation to understand how mutant SODs are more prone to losing zinc and why mutant SODs are dominant in inheritance. Aim 2 will assess how the concentrations of zinc-deficient SOD are modulated by CCS (the copper chaperone for SOD) and wild-type Cu,Zn SOD in transgenic animals ¿ both of which accelerate disease in vivo -- and how to most effectively pharmacologically decrease zinc-deficient SOD in vivo. Aim 3 will map the distribution of the different metal states of SOD in human sporadic ALS patients, testing whether zinc-deficient SOD may be the common connection between sporadic and familial SOD. Completion of the proposed experiments will critically test how SOD mutations lead to the development of ALS and whether loss of zinc (and/or copper) occurs from wild-type SOD in sporadic ALS. Project Narrative About 2% of patients with Lou Gehrig's disease (also known as ALS) carry mutations to a common antioxidant defense enzyme called SOD. We propose that this enzyme becomes toxic when it loses one zinc atom. We have developed new mass spectrometric methods that measure the loss of zinc directly from the spinal cord. Completion of the proposed experiments will help explain how SOD can be involved in the vast majority of ALS patients who do not have SOD mutations, which will point to new ways to treat the disease.

摘要

项目成果

Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.

• DOI: 10.1186/s12974-016-0620-9
• 发表时间: 2016-07-11
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Trias E;Ibarburu S;Barreto-Núñez R;Babdor J;Maciel TT;Guillo M;Gros L;Dubreuil P;Díaz-Amarilla P;Cassina P;Martínez-Palma L;Moura IC;Beckman JS;Hermine O;Barbeito L
• 通讯作者: Barbeito L