Disease modifying pathways in Niemann-Pick type C disease

描述（由申请人提供）：尼曼-匹克C病是一种常染色体隐性儿童神经退行性疾病，目前尚无有效治疗方法。这种疾病是由于细胞内胆固醇运输蛋白NPC1或NPC2的缺乏，导致晚期内体和溶酶体中胆固醇和糖脂的积累。这种细胞缺陷是如何导致神经退行性变的仍不得而知。补偿病理性脂质储存以促进神经元存活的过程是有希望的治疗靶点；然而，这些也同样没有得到很好的理解。因此，本应用程序的目的是确定调节尼曼-匹克C病神经退行性变严重程度的细胞通路。初步数据表明，自噬（细胞质蛋白质和细胞器的大量降解途径）在Niemann-Pick C病中上调。此外，我们的数据表明，微管相关蛋白tau的缺失显著增加了Niemann-Pick C小鼠模型的表型严重程度，并损害了npc1缺陷细胞的自噬。我的中心假设是自噬的诱导和tau病理的存在是Niemann-Pick C病发病机制的修饰因素。在我的第一个目标中，我将建立自噬在调节尼曼-皮克C病严重程度中的作用，并评估自噬作为治疗靶点。这将通过基因抑制和药理学增强Niemann-Pick C小鼠的自噬来实现，并评估这些操作对疾病表型的影响。在我的第二个目标中，我将定义tau对尼曼-皮克C病神经功能障碍的贡献。我假设功能性tau是NPC1缺陷细胞增加自噬所必需的。我将使用多种方法监测NPCI/tau双突变原代神经元培养中自噬通路的诱导和通量，并测试野生型和突变型人tau对这些细胞自噬缺陷的修复能力。进一步，我将确定人类tau蛋白在体内拯救自噬缺陷的能力以及Niemann-Pick C小鼠的表型。拟议研究的公共卫生相关性在于，它们将评估自噬作为Niemann-Pick C病的治疗靶点，并将阐明tau在神经病理学中的作用，从而提高我们对Niemann-Pick C和其他tau病（包括阿尔茨海默病和额颞叶痴呆）的神经退行性变的理解。

DESCRIPTION (provided by applicant): Niemann-Pick C disease is an autosomal recessive neurodegenerative disorder of childhood for which there is currently no effective treatment. This disorder results from deficiency of the intracellular cholesterol trafficking proteins NPC1 or NPC2, leading to the accumulation of cholesterol and glycolipids in late endosomes and lysosomes. How this cellular defect leads to neurodegeneration remains largely unknown. Processes compensating for pathologic lipid storage to promote neuronal survival represent promising therapeutic targets; however these are likewise not well understood. The objective of this application, therefore, is to identify cellular pathways that modulate the severity of neurodegeneration in Niemann-Pick C disease. This application is guided by preliminary data demonstrating that autophagy, a bulk degradation pathway for cytoplasmic proteins and organelles, is up-regulated in Niemann-Pick C disease. Additionally, our data demonstrate that deletion of the microtubule-associated protein tau markedly increases phenotypic severity of the Niemann-Pick C mouse model and impairs autophagy in NPC1-deficient cells. My central hypothesis is that the induction of autophagy and the presence of tau pathology are modifying factors in the pathogenesis of Niemann-Pick C disease. In my first Aim, I will establish the role of autophagy in modulating the severity of Niemann-Pick C disease, and evaluate autophagy as a therapeutic target. This will be accomplished by genetically inhibiting and pharmacologically enhancing autophagy in Niemann-Pick C mice, and assessing the effect of these manipulations on the disease phenotype. In my second Aim, I will define the contribution of tau to neurological dysfunction in Niemann-Pick C disease. I hypothesize that functional tau is required for increased autophagy in NPC1 deficient cells. I will use multiple assays to monitor the induction and flux of the autophagic pathway in NPCI/tau double-mutant primary neuronal cultures, and test the ability of wild type and mutant human tau to rescue autophagic defects in these cells. Further, I will determine the ability of human tau to rescue autophagic defects and the phenotype of Niemann-Pick C mice in vivo. The public health relevance of the proposed studies is that they will evaluate autophagy as a therapeutic target in Niemann-Pick C disease, and will elucidate the role of tau in neuropathology, thus improving our understanding of neurodegeneration in Niemann-Pick C and other tauopathies, including Alzheimer disease and the frontotemporal dementias. NOTE: The critiques of individual reviewers are provided in the following sections in an essentially unedited, verbatim form. They are provided to illustrate the range of opinions expressed. The application was discussed and assigned an overall score by all reviewers present. The critiques and the criterion scores were posted prior to the review meeting and may have not been updated or revised subsequent to the discussion at the meeting. Therefore, they may not represent the positions of the reviewers at the close of group discussion nor the final majority opinion of the group. The Resume and Summary of Discussion (above) represents the final outcome of the group discussion.