Abstract：
Niemann-Pick disease, type C (NPC) is a neurodegenerative, lysosomal storage disorder in individuals carrying two mutated copies of either the NPC1 or NPC2 gene. Consequently, impaired cholesterol recycling and an array of downstream events occur. Interestingly, in NPC, the hippocampus displays lysosomal lipid storage but does not succumb to progressive neurodegeneration as significantly as other brain regions. Since defining the neurodegeneration mechanisms in this disease is still an active area of research, we use mass spectrometry to analyze the overall proteome and phosphorylation pattern changes in the hippocampal region of a murine model of NPC. Using 3 week old mice representing an early disease time point, we observed changes in the expression of 47 proteins, many of which are consistent with the previous literature. New to this study, changes in members of the SNARE complex, including STX7, VTI1B, and VAMP7, were identified. Furthermore, we identified that phosphorylation of T286 on CaMKIIα and S1303 on NR2B increased in mutant animals, even at the late stage of the disease. These phosphosites are crucial to learning and memory and can trigger neuronal death by altering protein-protein interactions.
摘要：
尼曼-皮克病,C型（NPC）是一种神经退行性疾病，携带两个突变拷贝的NPC1或NPC2基因的个体的溶酶体贮积症。因此,受损的胆固醇再循环和一系列下游事件发生。有趣的是,在NPC,海马表现出溶酶体脂质储存，但不会像其他大脑区域那样明显地屈服于进行性神经变性。由于定义这种疾病的神经变性机制仍然是一个活跃的研究领域，我们使用质谱分析了NPC小鼠模型海马区的整体蛋白质组和磷酸化模式的变化.使用代表早期疾病时间点的3周龄小鼠，我们观察到47种蛋白质表达的变化，其中许多与以前的文献一致。这项研究的新手，SNARE复合体成员的变化，包括STX7、VTI1B、和VAMP7被鉴定。此外，我们发现，在突变动物中，CaMKIIα上的T286和NR2B上的S1303的磷酸化增加，即使在疾病的晚期。这些磷酸化位点对学习和记忆至关重要，可以通过改变蛋白质-蛋白质相互作用来触发神经元死亡。
