Role of PLD3 in nucleic acid recognition and brain function

这是一项研究磷脂酶D3（PLD 3）功能及其对 小鼠模型中的神经变性。PLD 3错义突变和表达不足已经被证实是一种基因突变。 与阿尔茨海默病（AD）和脊髓小脑共济失调有关，但 这些突变改变了哪些功能尚不清楚。PLD 3蛋白与神经炎性AD相关 噬菌斑，并已涉及Ab和Tau加工。我们最近发现， PLD 3和相关的蛋白质PLD 4不是磷脂酶，正如人们所认为的那样，但事实上是单一的磷脂酶。 位于内溶酶体中的单链DNA和RNA核酸外切酶。PLD 3和PLD 4可以强烈地 通过Toll样受体（TLR）影响核酸识别7、8和9。缺乏两种PLD 3 和PLD 4酶死于大量的自身炎症，而Pld 3-/-小鼠的表型是 相对微妙，尚未在老年小鼠中进行研究。在这里，我们建议研究的作用， 通过评估疾病相关的PLD 3等位基因的功能改变， 并通过生成工具来评估小胶质细胞中PLD 3和PLD 4缺乏的影响， 大脑的其他组织。

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.