Role of PLD3 in nucleic acid recognition and brain function

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已被 与阿尔茨海默病(AD)和脊髓小脑性共济失调有关，但其机制是通过 目前尚不清楚这些突变会改变哪些功能。PLD3蛋白与神经症性AD相关 斑块，并已牵涉到抗体和牛磺酸的处理。我们最近发现， PLD3和相关蛋白PLD4并不像人们认为的那样是磷脂酶，但实际上是单一的- DNA和RNA链状核酸外切酶定位于内溶酶体内。PLD3和PLD4可以强烈地 Toll样受体(TLR)7、8和9对核酸识别的影响 PLD4酶死于大量自体炎症，而Pld3-/-小鼠的表型是 相对微妙，还没有在老年小鼠身上进行研究。在这里，我们建议研究一下 通过评估疾病相关PLD3等位基因的功能变化来更详细地研究PLD3 并通过开发工具来评估PLD3和PLD4缺乏对小胶质细胞和 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.