Phospholipase D functional ablation has a protective effect in an Alzheimer's disease Caenorhabditis elegans model

Phospholipase D (PLD) is a key player in the modulation of multiple aspects of cell physiology and has been proposed as a therapeutic target for Alzheimer's disease (AD). Here, we characterize a PLD mutant, pld-1, using the Caenorhabditis elegans animal model. We show that pld-1 animals present decreased phosphatidic acid levels, that PLD is the only source of total PLD activity and that pld-1 animals are more sensitive to the acute effects of ethanol. We further show that PLD is not essential for survival or for the normal performance in a battery of behavioral tests. Interestingly, pld-1 animals present both increased size and lipid stores levels. While ablation of PLD has no important effect in worm behavior, its ablation in an AD-like model that overexpresses amyloid-beta (A beta), markedly improves various phenotypes such as motor tasks, prevents susceptibility to a proconvulsivant drug, has a protective effect upon serotonin treatment and reverts the biometric changes in the A beta animals, leading to the normalization of the worm body size. Overall, this work proposes the C. elegans model as a relevant tool to study the functions of PLD and further supports the notion that PLD has a significant role in neurodegeneration.