# Role of PLD3 in nucleic acid recognition and brain function

> **NIH NIH RF1** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $1,331,250

## Abstract

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.

## Key facts

- **NIH application ID:** 10525053
- **Project number:** 1RF1AG070775-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DAVID NEMAZEE
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,331,250
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525053

## Citation

> US National Institutes of Health, RePORTER application 10525053, Role of PLD3 in nucleic acid recognition and brain function (1RF1AG070775-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10525053. Licensed CC0.

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