Biochemical characterization and functional analysis of phospholipase D3 (PLD3)

Rare coding variants in the PLD3 gene coding for Phospholipase D3 were recently identified to increase the risk of developing late onset Alzheimer´s disease (LOAD). In order to address in more detail a possible influence of PLD3 on AD development, it was important to perform a fundamental biochemical characterization of PLD3 that provides a better understanding of its potential function. In this project evidence was provided that the type II transmembrane protein PLD3 is transported through the secretory and endocytic route to reach lysosomes. Using a newly described pathway, PLD3 is delivered to lysosomes via the endosomal sorting complex required for transport (ESCRT) machinery. An ubiquitination of PLD3 is required for its sorting into intraluminal vesicles of multivesicular bodies (MVBs). After fusion of MVBs with lysosomes, PLD3 is proteolytically processed into a stable luminal domain, to exert its main enzymatic function in this compartment. In the course of this project, PLD3 was identified as a lysosomal 5’ single-stranded acid exonuclease in immune cells. We could reveal that PLD3 is predominantly expressed in the brain, with highest expression in the hippocampus and the cerebral cortex. It could be further shown that PLD3 is the main 5’-exonuclease in the mouse brain. In Pld3-deficient mice, microglia alterations in the dentate gyrus of the hippocampus and the subventricular zone, both sites of adult neurogenesis, and a depression-like behavior were revealed. This suggests an important role of PLD3 in neuronal homeostasis, possibly affecting the onset and course of LOAD. Pld3 KO mice were bred with the 5xFAD Alzheimer´s disease (AD) mouse model. Although Pld3 was enriched in amyloid plaques (a hallmark of AD), no obvious changes on APP protein levels or cleavage products were observed in 5xFAD Pld3-/- mice, suggesting a more complex role of PLD3 in the etiology of AD.


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