PLD4

The PLD4 gene product, phospholipase D4 (Chr2-PD-L4), is a lysosome-membrane-associated protein exhibiting exonuclease activity. Primarily expressed in microglia and immune cells, it degrades extracellular nucleic acids, maintaining immune tolerance by preventing aberrant immune activation. Dysfunctional PLD4 correlates with autoimmune disorders, particularly systemic lupus erythematosus (SLE) and Sjögren's syndrome, where genetic variants impair self-nucleic acid clearance. Elevated PLD4 levels in cerebrospinal fluid are observed in Alzheimer's disease, suggesting neuroinflammatory involvement through microglial activation pathways.
Drug development remains preclinical, focusing on modulating nucleic acid degradation. NC-001, a small-molecule inhibitor, reduced autoantibodies in SLE murine models by blocking PLD4-mediated DNA fragmentation. A 2023 patent disclosed PLD4-X03, a monoclonal antibody targeting pathogenic nucleic acid-PLD4 complexes. Challenges persist due to PLD4's dual role in immune regulation and neuronal protection. Emerging single-cell transcriptomic studies reveal subtype-specific PLD4 expression patterns in disease microenvironments, guiding potential cell-targeted therapies. No clinical candidates have advanced beyond in vitro validation.