Role of PLD3 in nucleic acid recognition and brain function

PLD3在核酸识别和脑功能中的作用

• 批准号: 10525053
• 负责人: DAVID NEMAZEE
• 金额: $ 133.13万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525053
• 关键词: APP-PS1; Address; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Biochemical; Biological; Biological Assay; Brain; Cell Culture Techniques; Cells; Crystallization; DNA; Defect; Digestion; Disease; Double-Stranded RNA; Enzymes; Exonuclease; Genes; Genetic Polymorphism; Goals; Human; Immune system; Immunologics; Inflammation; Knock-in; Late Onset Alzheimer Disease; Ligands; Link; Measures; Microglia; Missense Mutation; Modeling; Mus; Mutation; Nerve Degeneration; Neurons; Nucleic Acids; Pathology; Phagocytes; Phenotype; Phospholipase; Phospholipases A; Proliferating; Proteins; RNA; Resources; Ribosomal RNA; Risk Factors; Role; Single-Stranded DNA; Spinocerebellar Ataxias; Structure; TLR3 gene; TLR7 gene; TLR8 gene; Testing; Thymus Gland; Toll-like receptors; Transgenes; Type 1 Spinocerebellar Ataxia; Variant; Vesicle; autoinflammation; brain tissue; genetic variant; genome wide association study; in vivo; mouse model; mutant; nervous system disorder; novel; null mutation; protein function; receptor; sensor; stressor; tau Proteins; tool; virtual

PROJECT SUMMARY/ABSTRACT This is a R01 proposal to study the function of Phospholipase D3 (PLD3) and its contribution to neurodegeneration in mouse models. PLD3 missense mutations and under expression have been implicated in Alzheimer's disease (AD) and in Spinocerebellar Ataxia, but the mechanisms by which these mutations alter function are unclear. PLD3 protein is associated with neuritic AD plaques and has been implicated in Ab and Tau processing. We have recently discovered that PLD3 and a related protein PLD4 are not phospholipases, as was thought, but are in fact single-stranded DNA and RNA exonucleases localized in endolysosomes. PLD3 and PLD4 can strongly influence nucleic acid recognition by Toll-like receptors (TLR) 7, 8 and 9. Mice lacking both PLD3 and PLD4 enzymes die of massive autoinflammation, whereas the phenotype of Pld3–/– mice is relatively subtle and has not been investigated in older mice. Here we propose to study the roles of PLD3 in more detail by evaluating functional alterations of disease associated PLD3 alleles and by generating tools to assess the effects of deficiency of PLD3 and PLD4 in microglia and other tissues of the brain. The ability of PLD3 deficiency to accelerate disease in the APP/PS1 model will also be investigated.

项目摘要/摘要 这是R01建议研究磷脂酶D3(PLD3)的功能及其对 小鼠模型的神经退行性变。PLD3错义突变和表达不足与 阿尔茨海默病(AD)和脊髓小脑性共济失调，但这些突变改变的机制 功能尚不清楚。PLD3蛋白与神经炎性AD斑块相关，并与抗体和 牛磺酸加工。我们最近发现PLD3和相关蛋白PLD4不是磷脂酶，因为 被认为是，但实际上是单链DNA和RNA外切酶定位在内溶酶体中。PLD3和 PLD4可以强烈影响Toll样受体(TLR)7、8和9的核酸识别。缺乏这三种受体的小鼠 PLD3和PLD4酶死于大量的自体炎症，而Pld3-/-小鼠的表型相对 这很微妙，还没有在年长的小鼠身上进行研究。在这里，我们建议更详细地研究PLD3的作用 通过评估疾病相关PLD3等位基因的功能变化和开发工具来评估 PLD3和PLD4缺乏对小胶质细胞和其他脑组织的影响。PLD3缺乏症的能力 为了加速APP/PS1模型中的疾病，也将进行调查。