Pathophysiology and potential therapy for a childhood neurodegenerative disease

儿童神经退行性疾病的病理生理学和潜在治疗

• 批准号: 8146933
• 负责人: Marquis T. Walker
• 金额: $ 5.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2012-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146933
• 关键词: 3 year old; Accounting; Apoptotic; Bone Marrow Transplantation; Brain; Bystander Effect; Cations; Cell Death; Cells; Characteristics; Child; Childhood; Chronic; Clinical; Defect; Diagnosis; Disease; Drosophila genus; Endocytosis; Excision; Functional disorder; Ganglioside Sialidase Deficiency Disease; Genes; Glean; Goals; Hematopoietic; Homologous Gene; Human; Invertebrates; Knock-out; Knockout Mice; Lysosomal Storage Diseases; Mental Retardation; Microglia; Modeling; Motor; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Organ; Pathogenesis; Patients; Phagocytes; Phenotype; Proteins; Research; Retinal Degeneration; Severities; Site; Testing; Tissues; Work; cytotoxic; fly; improved; insight; loss of function mutation; macrophage; motor impairment; mouse model; neuroinflammation; neuron loss; neurotoxicity; progressive neurodegeneration; public health relevance; receptor

DESCRIPTION (provided by applicant): The ~40 lysosomal storage diseases (LSDs) account for the most common cause of neurodegeneration in young children. One of these devastating LSDs, for which there is no treatment, is mucolipidosis type IV (MLIV). Patients with MLIV are diagnosed typically at about 1-3 years of age and display severe motor function deficits, mental retardation and retinal degeneration. The defects in lysosomal activity in MLIV patients are not exclusive to the central nervous system (CNS), but are observed in most organs and tissues. The pathogenesis underlying the clinical characteristics of MLIV is not clearly understood. MLIV arises from loss-of-function mutations in the human MCOLN1 gene, which disrupt the Mucolipin1 (TRPML1) protein. TRPML1 belongs to the Transient Receptor Potential (TRP) superfamily of cation channels, which include homologs in worms (cup-5), flies (trpml) and mice (Mcoln1 or TRPML1). Mutations that disrupt the function of the TRPML1 homolog in both invertebrate models disrupt lysosomal function. Most recently, analysis of the Drosophila trpml knockout demonstrates that the progressive neurodegeneration and motor impairment result from a defect in the removal of early apoptotic neurons in the brain, which leads to accumulation of late apoptotic neurons, release of cytotoxic cellular contents and cell death in the adjacent cells. The progressive neurodegeneration, due to this bystander effect, and the ensuing motor defects are suppressed by expression of the wild-type trpml+ gene in macrophages. Here, I propose to focus on a MLIV mouse model to test concepts concerning the pathogenesis of neurodegeneration, which we have gleaned from the Drosophila model. In addition, I propose to test whether bone marrow transplantation will reduce the severity of the phenotype. This proposal is feasible since I have obtained the recently generated mouse model (TRPML1-/-) that recapitulates clinical manifestations of MLIV. Moreover, I started characterizing the TRPML1-/- mice and found that they display progressive neurodegeneration in the brain and motor defects. Aim one is to test the hypothesis that the hematopoietic phagocytes in the TRPML1-/- mice are defective in endocytosis and lysosomal dependent degradation. Aim two is to test the hypotheses that the TRPML1-/- knockout mice display chronic neuroinflammation, which contributes to neurotoxicity. I suggest that my proposed study will provide insight into how neuroinflammation contributes to the progression of a broad range of neurodegenerative conditions. The third and most important aim is to test the hypothesis that bone marrow transplantation in the TRPML1-/- knockout will suppress the severity of the neurodegeneration. If so, this would raise the possibility that bone marrow transplantation may be a treatment for MLIV. Finally, the findings from the proposed study on the mouse MLIV model may provide insights into the mechanisms underlying the progressive neuronal cell death that characterize a broad range of neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The proposed research is aimed at understanding the cellular mechanisms that are involved in MLIV neurodegeneration. MLIV is a devastating childhood disease which lacks any treatment for the disease, I am testing BMT as a viable treatment for suppressing neurodegeneration in MLIV patients. This proposed work is relevant to the understanding and treatment of MLIV, and to improving the lives of MLIV patients.

描述(由申请人提供)：约40种溶酶体储存性疾病(LSD)是导致幼儿神经变性的最常见原因。其中一种破坏性的LSD是IV型粘脂病(MLIV)，目前尚无治疗方法。MLIV患者通常在大约1-3岁时被诊断出来，表现出严重的运动功能障碍、智力低下和视网膜变性。MLIV患者的溶酶体活性缺陷不仅存在于中枢神经系统(CNS)，而且在大多数器官和组织中都可观察到。MLIV的临床特征的发病机制尚不清楚。MLIV由人类MCOLN1基因功能丧失突变引起，这种突变破坏了Mucolipin1(TRPML1)蛋白。TRPML1属于瞬时受体电位(TRP)超家族阳离子通道，包括蠕虫(CUP-5)、苍蝇(TRPML1)和小鼠(Mcoln1或TRPML1)的同源物。在这两种无脊椎动物模型中，破坏TRPML1同源基因功能的突变会破坏溶酶体功能。最近，对果蝇trpm1基因敲除的分析表明，进行性神经变性和运动障碍是由于大脑中早期凋亡神经元的移除缺陷导致的，这导致了晚期凋亡神经元的积聚，细胞毒内容物的释放和邻近细胞的死亡。这种旁观者效应导致的进行性神经变性和随后的运动缺陷被巨噬细胞中野生型trpml+基因的表达抑制。在这里，我建议将重点放在MLIV小鼠模型上，以测试我们从果蝇模型中收集到的关于神经退行性变发病机制的概念。此外，我建议测试骨髓移植是否会降低表型的严重程度。这个建议是可行的，因为我已经获得了最近产生的概括MLIV临床表现的小鼠模型(TRPML1-/-)。此外，我开始描述TRPML1-/-小鼠的特征，发现它们的大脑表现出进行性的神经退化和运动缺陷。目的一是验证TRPML1-/-小鼠的造血吞噬细胞在内吞和溶酶体依赖性降解方面存在缺陷的假说。目的二是验证TRPML1-/-基因敲除小鼠表现出慢性神经炎症的假说，这是导致神经毒性的原因。我认为我提议的研究将对神经炎症如何促进一系列神经退行性疾病的进展提供洞察力。第三个也是最重要的目的是检验这样一个假设，即在TRPML1-/-基因敲除的情况下进行骨髓移植将抑制神经退行性变的严重程度。如果是这样，这将增加骨髓移植可能是MLIV的一种治疗方法的可能性。最后，对小鼠MLIV模型的拟议研究结果可能为揭示一系列神经退行性疾病的特征的进行性神经细胞死亡的潜在机制提供洞察力。 公共卫生相关性：拟议的研究旨在了解MLIV神经变性所涉及的细胞机制。MLIV是一种毁灭性的儿童疾病，缺乏任何治疗方法，我正在测试BMT作为一种可行的治疗方法来抑制MLIV患者的神经变性。这项拟议的工作对于了解和治疗MLIV，以及改善MLIV患者的生活具有重要意义。