Aberrant Protein Kinase C Signaling in Alzheimer's Disease

阿尔茨海默病中的异常蛋白激酶 C 信号转导

• 批准号: 10901015
• 负责人: Kim Bohemie Dore
• 金额: $ 90.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901015
• 关键词: AMPA Receptors; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Automobile Driving; Binding; Biochemical; Biological Markers; Biosensor; Brain; Brain Diseases; Brain region; Cognition; DLG1 gene; DLG4 gene; Data; Dementia; Diglycerides; Disease; Electrophysiology (science); Enzymes; Event; Family; Functional disorder; Genes; Germ-Line Mutation; Goals; Homeostasis; Image; Impaired cognition; Impairment; Individual; Inflammatory; Isoenzymes; Late Onset Alzheimer Disease; Learning; Ligands; Malignant Neoplasms; Measures; Mediating; Memory; Methods; Microglia; Molecular; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurons; PRKCA gene; Pathway Analysis; Phosphorylation; Play; Protein Analysis; Protein Kinase; Protein Kinase C; Proteins; Proteomics; Public Health; Research; Role; Scaffolding Protein; Second Messenger Systems; Senile Plaques; Signal Pathway; Signal Transduction; Signaling Protein; Site; Surface; Synapses; Synaptic Receptors; Synaptic Transmission; Testing; Therapeutic; Variant; Vision; affection; age related; brain size; cancer clinical trial; design; disease phenotype; extracellular; fluorescence lifetime imaging; genome editing; genome sequencing; genome wide association study; kinase inhibitor; mouse model; neuron loss; neurotransmission; novel therapeutic intervention; phosphoproteomics; protein function; protein kinase C kinase; rare variant; scaffold; segregation; synaptic depression; synaptic function; therapeutic target; whole genome

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.

摘要/摘要 我们提出的研究的总体视野是了解分子，细胞和电生理学 蛋白激酶C（PKC）通过异常信号传导的机制促进了阿尔茨海默氏症的病理 疾病（AD）。这种与年龄相关的痴呆的特征是解除受管的信号传导，突触的变性， 神经元死亡，最终减少了学习和记忆中涉及的大脑区域的大小。尽管 大量努力已致力于了解细胞外淀粉样β（Aβ）斑块的作用 新兴的证据指出，PKC同工酶发挥了疾病的标志，表明发出的信号传导 在该疾病中的潜在病因作用。我们已经组建了一支拥有广泛和完善的团队 PKC机制和突触机制方面的专业知识，以了解异常PKC信号如何贡献 疾病表型。最近搜索与整个基因组的AD相关的稀有功能变体 来自晚期AD家族的数据的测序数据已经确定了两者的基因中的高渗透变体 PKC（PRKCA）和PKC（PRKCH）在多个家庭中与广告情感地位共处。所有pkc 变体显示增强的活动，我们对一个变体（PKCM489V）的详细分析已经确定了这一点 重新连接脑磷蛋白质组，驱动突触变性并损害认知 鼠标模型。增强的PKC功能驱动AD病理学与无偏的磷光蛋白质组学一致 分析已确定升高的PKC信号传导是AD患病大脑中最早的事件之一。那， 推动该建议的假设是两个PKC同工酶，神经元中的PKC和小胶质细胞中的PKC，播放 在大脑体内稳态中的基本作用以及对任何一种导致AD病理的影响。我们的目标 结合最先进的蛋白质组学，生化，成像和电生理方法，以便为了 研究分子机制如何影响神经元或小胶质细胞功能的异常信号传导。 我们还将检验以下假设：升高的任何一个PKC的蛋白质水平是AD中的生物标志物。这个项目 应该在我们对神经变性和广告的理解方面取得了长足的进步，并提供可能 针对这种毁灭性疾病的新治疗策略。