Aberrant Protein Kinase C Signaling in Alzheimer's Disease

摘要/摘要 我们提出的研究的总体愿景是了解分子、细胞和电生理 蛋白激酶C(PKC)异常信号促进阿尔茨海默病的病理机制 疾病(AD)。这种老年性痴呆的特征是信号失控，突触变性， 神经元死亡，最终导致参与学习和记忆的大脑区域缩小。而当 人们一直致力于了解细胞外淀粉样蛋白-β(A-β)斑块的作用 作为该病的一个标志，新出现的证据表明，通过PKC同工酶发挥作用的信号失控 在疾病中可能起到致病作用。我们组建了一支具有广泛互补性的团队 在PKC机制和突触机制方面的专业知识，以了解异常的PKC信号如何起作用 对疾病表型的影响。最近从全基因组中寻找与AD相关的罕见功能变异 来自晚发性阿尔茨海默病家系的测序数据发现，这两个基因都存在高度渗透性变异 PKC(PrKca)和PKC(Prkch)在多个共分离的AD情感状态家系中的表达。所有PKC 变异体显示出增强的活性，我们对一个变异体(PKCM489V)的详细分析已经确定 它足以重新连接大脑磷酸蛋白质组，驱动突触退化，并损害认知。 老鼠模型。推动AD病理的PKC功能增强与无偏倚的磷酸蛋白质组学一致 分析发现，PKC信号升高是阿尔茨海默病患者大脑中最早的事件之一。因此， 支持这一观点的假设是两种PKC同工酶，神经元中的PKC和小胶质细胞中的PKC发挥作用 在大脑动态平衡中的重要作用，放松对两者的调控都有助于AD的病理。我们的目标是 将最先进的蛋白质组学、生化、成像和电生理方法结合在一起，以便 研究PKC或PKC异常信号如何影响神经元或小胶质细胞功能的分子机制。 我们还将检验这一假设，即PKC蛋白水平的增加是AD的一个生物标记物。这个项目 应该在我们对神经退行性变和阿尔茨海默病的理解上取得重大进展，并为 针对这种毁灭性疾病的新治疗策略。

Summary/Abstract The overall vision of our proposed research is to understand the molecular, cellular and electrophysiological mechanisms by which aberrant signaling by protein kinase C (PKC) promotes the pathology of Alzheimer’s Disease (AD). This age-related dementia is characterized by deregulated signaling, degeneration of synapses, neuronal death and, ultimately, a reduction in the size of brain regions involved in learning and memory. While significant efforts have been devoted to understanding the role of extracellular amyloid-β (Aβ) plaques that are a hallmark of the disease, emerging evidence points to deregulated signaling by PKC isozymes playing a potentially causative role in the disease. We have assembled a team with extensive and complementary expertise in PKC mechanisms and synaptic mechanisms to understand how aberrant PKC signaling contributes to the disease phenotype. Recent searches for rare functional variants associated with AD from whole genome sequencing data from families with late-onset AD have identified highly penetrant variants in the genes for both PKC (PRKCA) and PKC (PRKCH) in multiple families that co-segregate with AD affection status. All PKC variants display enhanced activity, and our detailed analysis of one variant (PKC M489V) has established that it is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. Enhanced PKC function driving AD pathology is consistent with unbiased phosphoproteomics analysis that have identified elevated PKC signaling as one of the earliest events in AD diseased brains. Thus, the hypothesis driving this proposal is that two PKC isozymes, PKC in neurons and PKC in microglia, play essential roles in brain homeostasis and that deregulation of either contributes to the pathology of AD. We aim to combine state-of-the-art proteomics, biochemical, imaging and electrophysiological approaches in order to study molecular mechanisms of how aberrant signaling by PKC or PKC impact neuronal or microglial function. We also will test the hypothesis that increased protein levels of either PKC is a biomarker in AD. This project should make significant strides in our understanding of neurodegeneration and AD as well as providing possible new therapeutic strategies against this devastating disease.