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.

Variants of the PLD3 gene have been associated with Alzheimer's disease and other brain defects but the function of the protein encoded by this gene has not previously been known. We recently found that its enzymatic function involves digestion of DNA and RNA in vesicles within cells. Our studies will assess the connection between PLD3 function and its broader effects in disease.