Pathophysiology and potential therapy for a childhood neurodegenerative disease

描述（由申请人提供）：约40种溶酶体贮积病（LSD）是幼儿神经变性的最常见原因。这些毁灭性的LSD之一，没有治疗方法，是粘脂沉积症IV型（MLIV）。患有MLIV的患者通常在约1-3岁时被诊断，并显示严重的运动功能缺陷、智力迟钝和视网膜变性。MLIV患者的溶酶体活性缺陷并不局限于中枢神经系统（CNS），而是在大多数器官和组织中观察到。MLIV临床特征的发病机制尚不清楚。 MLIV是由人类MCOLN 1基因的功能缺失突变引起的，这种突变破坏了Mucolipin 1（TRPML 1）蛋白。TRPML 1属于瞬时受体电位（TRP）阳离子通道超家族，该家族包括蠕虫（cup-5）、苍蝇（trpml）和小鼠（Mcoln 1或TRPML 1）中的同源物。在两种无脊椎动物模型中破坏TRPML 1同源物功能的突变破坏溶酶体功能。最近，对果蝇trpml敲除的分析表明，进行性神经变性和运动障碍是由脑中早期凋亡神经元去除缺陷引起的，这导致晚期凋亡神经元的积累、细胞毒性细胞内容物的释放和相邻细胞中的细胞死亡。进行性神经变性，由于这种旁观者效应，和随之而来的运动缺陷被抑制的野生型trpml+基因在巨噬细胞中的表达。 在这里，我建议集中在MLIV小鼠模型，以测试有关的神经退行性疾病的发病机制的概念，我们已经收集到的果蝇模型。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生成的小鼠模型（TRPML 1-/-），概括了MLIV的临床表现。此外，我开始描述TRPML 1-/-小鼠，发现它们在大脑和运动缺陷中表现出进行性神经变性。目的一是验证TRPML 1-/-小鼠的造血吞噬细胞内吞和溶酶体依赖性降解缺陷的假设。目的二是验证TRPML 1-/-敲除小鼠表现出慢性神经炎症，这有助于神经毒性的假设。我建议我提出的研究将提供深入了解神经炎症如何有助于广泛的神经退行性疾病的进展。第三个也是最重要的目的是检验TRPML 1-/-敲除的骨髓移植将抑制神经变性的严重程度的假设。如果是这样的话，这将提高骨髓移植可能是MLIV治疗的可能性。最后，对小鼠MLIV模型的拟议研究的结果可能会提供深入了解进行性神经元细胞死亡的机制，这些机制是广泛的神经退行性疾病的特征。 公共卫生相关性：拟议的研究旨在了解参与MLIV神经变性的细胞机制。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作为抑制MLIV患者神经变性的可行治疗方法。这项拟议的工作与MLIV的理解和治疗以及改善MLIV患者的生活有关。

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.