FUNCTION OF AN ALZHEIMER DISEASE-RELATED PROTEIN

描述：(改编自申请者摘要)：本报告的目标 建议确定神经元蛋白Synelfin的正常功能 大量存在于成年脊椎动物的端脑中。Synelfin已经被 独立于几个物种，包括人类，在那里它有 被称为NACP(非淀粉样β成分前体) 提示其与最近从淀粉样蛋白中提纯的一种新多肽的关系 阿尔茨海默病(AD)中的斑块。对鸣禽的研究表明，这一点 高度保守的蛋白质在正常情况下有一个特殊但尚未确定的作用 突触可塑性的调节。要深入了解正常函数 对于Synelfin，提出了三个研究目标：1)进行生化 对Synelfin具有功能关系的假设进行检验的研究 通过对保守结构的观察表明，与载脂蛋白有关 功能。Synelfin蛋白的正常和突变形式将在 并分析了它们与磷脂的相互作用。 以载脂蛋白的特征行为作为比较点。 2)确定蛋白质中与其有关的结构元素 突触前终末的堆积。突变的DNA结构将是 将其导入原代培养的海马神经元，并编码 蛋白质将通过免疫荧光进行定位。这些研究可能会给出 洞察蛋白质的明显模块结构，并帮助 用于鉴定与Synelfin结合的其他蛋白质的实验设计 互动。 3)在转基因小鼠中过表达Synelfin蛋白并检测其作用 神经解剖学和神经功能。这将检验这一假设 Synelfin的结构性增加是否会促进 阿尔茨海默病样神经病理，或改变发育或行为 依赖于神经可塑性的过程。

DESCRIPTION: (Adapted from Applicant's Abstract): The goal of this proposal is to determine the normal function of synelfin, a neuronal protein abundant in the adult vertebrate telencephalon. Synelfin has been independently isolated from several species, including humans, where it has been referred to as NACP (the Non-Amyloid beta-Component Precursor) to indicate its relationship to a novel peptide recently purified from amyloid plaques in Alzheimer Disease (AD). Studies in songbirds suggest that this highly-conserved protein has a specific but yet-undefined role in the normal regulation of synaptic plasticity. To gain insight into the normal function of synelfin, three research aims are proposed: 1) conduct biochemical studies to test the hypothesis that synelfin has a functional relationship to apolipoproteins, as suggested by observation of conserved structural features. Normal and mutated forms of synelfin protein will be expressed in E.coli and analyzed for their interactions with phospholipids, using the well-characterized behavior of apoliopoproteins as a point of comparison. 2) determine the structural elements in the protein responsible for its accumulation at presynaptic terminals. Mutated DNA constructs will be introduced into primary cultured hippocampal neurons, and the encoded proteins will be localized by immunofluorescence. These studies may give insight into the apparent modular structure of the protein, and help in the design of experiments to identify other proteins with which synelfin interacts. 3) overexpress the synelfin protein in transgenic mice and assay the effect on neuroanatomy and neurological function. This will test the hypothesis whether a constitutive increase in synelfin will promote the development of Alzheimer-like neuropathology, or alter developmental or behavioral processes that depend upon neural plasticity.