The amelioration of peroxisomal disorders due to defects in Pex10

项目摘要/摘要 过氧酶体是一种含有酶的膜细胞器，参与活性物质的解毒作用。 氧物种、超长链脂肪酸的分解代谢和血浆原的生物合成。病人 伴有过氧化物症的生物发生障碍(PBD)表现为神经缺陷，从严重疾病到 Zellweger综合征，出生后六个月内致命，可导致进行性小脑性共济失调 和脊髓性共济失调。尽管一些PBD患者在出生时就可以观察到神经功能障碍，但 这种疾病的胚胎学病因学还没有被探索。此外，目前还没有有效的治疗方法 预防或改善PBD患者的神经退行性变。 在小鼠身上，我们发现了过氧化物体基因Pex10的突变。生物标志物在诊断中的应用 在Pex10小鼠模型中，人类的PBD的表达也受到了类似的干扰。此外，Pex10突变小鼠胚胎 表现出进行性的行动不便。因此，我们的Pex10突变体为研究Pex10提供了一个很好的范例 PBD神经病理学和第一个脊椎动物Pex10模型。对Pex10突变胚胎的分析显示存在缺陷 运动神经和肌肉之间的连通性。这些初步数据为这一点提供了基础 R21建议了解神经缺陷的胚胎学起源并探索可能的 在这种过氧酶体动物模型中，延长寿命和改善神经病理的治疗方法。 目的1将新的Pex10小鼠突变体描述为PBD进行性共济失调的模型。我们会 检验胚胎中过氧化体功能改变抑制轴突终止的假设 突触，它扰乱了运动电路的连接。我们将确定进步的 胚胎运动丧失是由于髓鞘形成、轴突引导和/或突触功能缺陷所致。 脊髓神经元。目标2将首次定义胎儿中的过氧化物体蛋白质组，并将 测定Pex10突变体中过氧化物酶含量的变化，特别是髓鞘形成过程中的变化 雪旺细胞。此外，我们将确定PEX10锌环指的点突变是否会中断 泛素化活性，这可能改变过氧化体受体的循环。Aim 3将使用Pex10鼠标 评估延长寿命和挽救神经元表型的可能治疗策略的模型 在突变的小鼠身上。总体而言，这些研究将首次深入了解PBD的胚胎学起源 并将寻求确定潜在的治疗方法来减轻严重的神经退行性缺陷 这是过氧化物性疾病的基础。

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.