The amelioration of peroxisomal disorders due to defects in Pex10

Pex10 缺陷导致的过氧化物酶体疾病的改善

• 批准号: 8620144
• 负责人: Lee A. Niswander
• 金额: $ 19.32万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620144
• 关键词: Adult; Aging; Amino Acids; Anabolism; Animal Model; Ataxia; Axon; Bile Acids; Biogenesis; Biological Markers; Birth; Catabolism; Cells; Cerebellar Ataxia; Cessation of life; Cholesterol; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Drug Metabolic Detoxication; Embryo; Enzymes; Etiology; Fetal Development; Fetus; Fingers; Future; Genes; Genetic; Goals; Growth; Human; Hydrogen Peroxide; Intelligence; Lead; Link; Longevity; Malignant Neoplasms; Membrane; Metabolic; Modeling; Mono-S; Motor; Mus; Muscle; Muscle Tonus; Mutant Strains Mice; Mutation; Myelin; Neonatal Adrenoleukodystrophy; Nerve; Nerve Degeneration; Neurologic; Neurons; Neuropathy; Obesity; Organelles; Pathology; Patients; Peroxisomal Disorders; Phenotype; Phospholipids; Physiology; Plasmalogens; Point Mutation; Polyamines; Polyunsaturated Fatty Acids; Process; Progressive Disease; Proteome; Reactive Oxygen Species; Recycling; Schwann Cells; Spinal; Staging; Synapses; Testing; Therapeutic; Therapeutic Studies; Translating; Ubiquitination; Very Long Chain Fatty Acid; Zellweger Syndrome; Zinc; axon guidance; base; effective therapy; fatty acid biosynthesis; fetal; high reward; insight; limb movement; locomotor deficit; mouse model; mutant; myelination; neuropathology; novel; peroxisome; prevent; public health relevance; receptor; respiratory; synaptic function; synaptogenesis; ubiquitin-protein ligase

Project Summary/Abstract Peroxisomes are enzyme-containing membrane organelles that are involved in the detoxification of reactive oxygen species, the catabolism of very long chain fatty acids and the biosynthesis of plasmalogens. Patients with peroxisomal biogenesis disorders (PBD) show neurological defects ranging from the severe disease Zellweger syndrome that is lethal within six months of birth, to the progressive diseases of cerebellar ataxia and spinal ataxia. Despite the fact that neurological deficits can be observed at birth in some PBD patients, the embryological etiology of the disease has not been explored. Moreover, there are no effective therapies to prevent or ameliorate the neural degeneration that occurs in PBD patients. In mice we have identified a mutation in the peroxisomal gene Pex10. Biomarkers utilized for diagnosis of PBD in humans are similarly disrupted in the Pex10 mouse model. Moreover, Pex10 mutant mouse embryos show a progressive inability to move. Thus, our Pex10 mutant provides an excellent paradigm for the study of PBD neuropathology and the first vertebrate Pex10 model. Analysis of Pex10 mutant embryos shows defects in the connectivity between the motor nerves and the muscle. These preliminary data provide the basis for this R21 proposal to understand the embryological origin of the neurological deficits and to explore possible therapies to increase the lifespan and ameliorate the neuropathology in this peroxisomal animal model. Aim 1 will characterize the novel Pex10 mouse mutant as a model for PBD progressive ataxia. We will test the hypothesis that alterations in peroxisomal function in the embryo inhibit termination of axons at the synapse which disrupts the connectivity of the locomotor circuit. We will determine whether the progressive embryonic locomotor loss results from defects in myelination, axon guidance and/or synapse function of the spinal neurons. Aim 2 will provide the first definition of the peroxisomal proteome in the fetus and will determine the changes in the contents of the peroxisome in Pex10 mutants, in particular in the myelinating Schwann cells. Moreover, we will determine whether the point mutation in the PEX10 zinc RING finger disrupts ubiquitination activity, which could alter recycling of the peroxisomal receptor. Aim 3 will use the Pex10 mouse model to evaluate possible therapeutic strategies to increase the lifespan and rescue the neuronal phenotypes in mutant mice. Overall these studies will provide the first insight into the embryological origin of PBD neuropathies and will seek to define potential therapies to alleviate the profound neurodegenerative defects that underlie peroxisomal diseases.

项目摘要/摘要 过氧化物酶体是含酶的膜细胞器，与反应性排毒有关 氧，长链脂肪酸的分解代谢和浆元的生物合成。患者 过氧化物酶体生物发生障碍（PBD）显示出从严重疾病的神经缺陷 Zellweger综合征在出生后六个月内致命，对小脑共济失调的进行性疾病 和脊柱共济失调。尽管在某些PBD患者中可以观察到神经系统缺陷，但 尚未探讨该疾病的胚胎学病因。而且，没有有效的疗法 预防或改善PBD患者发生的神经变性。 在小鼠中，我们已经确定了过氧化物酶体基因PEX10中的突变。用于诊断的生物标志物 PEX10小鼠模型中类似地破坏了人类的PBD。此外，PEX10突变小鼠胚胎 表现出渐进的行动。因此，我们的PEX10突变体为研究提供了极好的范式 PBD神经病理学和第一个脊椎动物PEX10模型。 PEX10突变胚胎的分析显示缺陷 在运动神经与肌肉之间的连通性中。这些初步数据为此提供了基础 R21的建议，以了解神经缺陷的胚胎学起源并探索可能 在这种过氧化物酶体模型中，可以增加寿命并改善神经病理学的疗法。 AIM 1将将新型PEX10小鼠突变体描述为PBD进行性共济失调的模型。我们将 检验以下假设：胚胎中过氧化物酶体功能的改变抑制轴突在 突触破坏了运动电路的连通性。我们将确定渐进式 胚胎运动损失是由于髓鞘形成，轴突引导和/或突触功能的缺陷而导致的 脊柱神经元。 AIM 2将提供胎儿过氧化物酶体蛋白质组的第一个定义，将 确定PEX10突变体中过氧化物酶体内容的变化，特别是在骨髓中 Schwann细胞。此外，我们将确定PEX10锌环手指中的点突变是否会破坏 泛素化活性可能会改变过氧化物酶体受体的回收利用。 AIM 3将使用PEX10鼠标 模型以评估可能增加寿命并营救神经元表型的治疗策略 在突变小鼠中。总的来说，这些研究将提供对PBD胚胎学起源的首次见解 神经病，并将寻求定义潜在的疗法以减轻深刻的神经退行性缺陷 这是过氧化物酶体疾病的基础。