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愿景是了解分子、细胞和电生理学 蛋白激酶 C (PKC) 的异常信号传导促进阿尔茨海默病病理的机制 这种与年龄相关的痴呆症的特征是信号传导失调、突触退化、 神经死亡，并最终导致涉及学习和记忆的大脑区域尺寸减小。 重要的研究人员致力于了解细胞外淀粉样蛋白-β (Aβ) 斑块的作用，这些斑块 作为该疾病的一个标志，新出现的证据表明 PKC 同工酶的信号传导失调，在 我们组建了一个具有广泛和互补性的团队。 PKC 机制和突触机制方面的专业知识，以了解异常 PKC 信号传导如何发挥作用 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 AD 家族的测序数据高度鉴定了这两种疾病的基因中的渗透性变异 多个家庭中的 PKC (PRKCA) 和 PKC (PRKCH) 与 AD 患病状态共分离 所有 PKC。 变体显示出增强的活性，我们对一种变体 (PKC M489V) 的详细分析表明： 它足以重新连接大脑磷酸化蛋白质组、驱动突触变性并损害认知能力 增强的 PKC 功能驱动 AD 病理学与无偏磷酸蛋白质组学一致。 分析表明 PKC 信号传导升高是 AD 患病大脑中最早发生的事件之一。 推动这一提议的假设是，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 我们的目标是在大脑稳态中发挥重要作用，而其中任何一个的失调都会导致 AD 的病理学。 结合最先进的蛋白质组学、生化、成像和电生理学方法， 研究 PKC 或 PKC 的异常信号传导如何影响神经或小胶质细胞功能的分子机制。 我们还将测试以下假设：PKC 的蛋白质水平升高是 AD 的生物标志物。 应该在我们对神经退行性变和 AD 的理解方面取得重大进展，并提供可能 针对这种毁灭性疾病的新治疗策略。