Microarray analysis in Npc1-/- mouse cerebellum

Niemann-Pick Type C disease is an autosomal recessive neurodegenerative disorder with abnormal lipid storage as the major cellular pathologic hallmark. Genetic analyses have identified mutations in NPC1 gene in the great majority of cases, while mutations in NPC2 account for the remainders. Yet, little is known regarding the cellular mechanisms responsible for NPC pathogenesis, especially for neurodegeneration, which is the usual cause of death. To identify critical steps that could account for the pathological manifestations of the disease in one of the most affected brain structures, we performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Our results provide novel molecular insight regarding the mechanisms of pathogenesis in NPC disease and reveal potential new therapeutic targets. We performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Differentially-expressed genes identified by both microarray platforms were then subjected to KEGG pathway analysis. Expression of genes in six pathways was significantly altered in Npc1-/- mice; functionally, these signaling pathways belong to the following three categories: 1) steroid and terpenoid biosynthesis, 2) immune response, and 3) cell adhesion/motility. In addition, the expression of several proteins involved in lipid transport was significantly altered in Npc1-/- mice.尼曼-匹克C型病（Niemann-Pick Type C disease）是一种常染色体隐性神经退行性疾病，以异常脂质贮积为核心细胞病理特征。遗传学分析显示，绝大多数病例可检出NPC1基因（NPC1 gene）突变，剩余病例则由NPC2基因突变所致。目前学界对该病发病机制的细胞层面机制仍知之甚少，尤其是作为主要致死原因的神经退行性变相关机制。为明确该病在最易受累的脑结构之一中病理表现的关键环节，我们采用安捷伦（Agilent）、因美纳（Illumina）两种不同的微阵列芯片平台，对三周龄Npc1+/+与Npc1-/-小鼠的小脑组织开展全基因表达分析。本研究结果为尼曼-匹克C型病的发病机制提供了全新的分子视角，并揭示了潜在的新型治疗靶点。随后，我们对两种芯片平台共同鉴定出的差异表达基因进行KEGG通路分析（KEGG pathway analysis）。结果显示，Npc1-/-小鼠体内6条通路的基因表达存在显著改变；功能层面，这些信号通路可归为以下三类：1) 类固醇与萜类生物合成通路，2) 免疫应答通路，3) 细胞黏附/运动通路。此外，Npc1-/-小鼠体内多种参与脂质转运的蛋白质表达亦出现显著异常。