Downregulation of RBO-PI4KIIIα Facilitates Aβ42Secretion and Ameliorates Neural Deficits in Aβ42-ExpressingDrosophila
Journal of Neuroscience
Phosphoinositides and their metabolizing enzymes are involved in A␤ 42 metabolism and Alzheimer's disease pathogenesis. In yeast and mammals, Eighty-five requiring 3 (EFR3), whose Drosophila homolog is Rolling Blackout (RBO), forms a plasma membrane-localized protein complex with phosphatidylinositol-4-kinase Type III␣ (PI4KIII␣) and a scaffold protein to tightly control the level of plasmalemmal phosphatidylinositol-4-phosphate (PI 4 P). Here, we report that RBO binds to Drosophila PI4KIII␣,
... sophila PI4KIII␣, and that in an A␤ 42 -expressing Drosophila model, separate genetic reduction of PI4KIII␣ and RBO, or pharmacological inhibition of PI4KIII␣ ameliorated synaptic transmission deficit, climbing ability decline, premature death, and reduced neuronal accumulation of A␤ 42 . Moreover, we found that RBO-PI4KIIIa downregulation increased neuronal A␤ 42 release and that PI4P facilitated the assembly or oligomerization of A␤ 42 in/on liposomes. These results indicate that RBO-PI4KIIIa downregulation facilitates neuronal A␤ 42 release and consequently reduces neuronal A␤ 42 accumulation likely via decreasing A␤ 42 assembly in/on plasma membrane. This study suggests the RBO-PI4KIII␣ complex as a potential therapeutic target and PI4KIII␣ inhibitors as drug candidates for Alzheimer's disease treatment. the project, designed, and participated in all experiments except the cell culture studies; X.Z. designed and participated in experiments of flies, cells, WB, co-IP, and liposome; W.-A.W. firstly obtained the quantitative data of fly behavior; L.-X.J. studied the effect of compounds on A␤ 42 secretion, secretases' activity, and Phosphoinositides and their metabolizing enzymes are involved in A␤ 42 metabolism and Alzheimer's disease pathogenesis. Here, in an A␤ 42 -expressing Drosophila model, we discovered and studied the beneficial role of downregulating RBO or its interacting protein PI4KIII␣Oa protein that tightly controls the plasmalemmal level of PI 4 POagainst the defects caused by A␤ 42 expression. Mechanistically, RBO-PI4KIII␣ downregulation reduced neuronal A␤ 42 accumulation, and interestingly increased neuronal A␤ 42 release. This study suggests the RBO-PI4KIII␣ complex as a novel therapeutic target, and PI4KIII␣ inhibitors as new drug candidates.