Phosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in glia

Abstract

Glial engulfment of degenerating neuronal material is essential for nervous system development, maintenance and repair. Genome-wide association studies have identified protective variants in the phosphoinositide-metabolising enzyme PLCG2 that modify Alzheimers disease risk, but how PLCG2-dependent phosphoinositide signalling regulates glial engulfment remains unclear. Using Drosophila, we investigated the role of small wing (sl), the fly orthologue of human PLCG2, in glial responses to axonal injury and amyloid pathology. Glial knockdown of sl altered immune-associated transcriptional pathways and significantly delayed clearance of degenerating olfactory receptor neuron axons following axotomy. Loss of sl disrupted injury-induced phosphoinositide remodelling, resulting in elevated basal PIP2 levels and impaired post-injury accumulation of PIP3. Similar defects were observed following knockdown of the engulfment receptor Draper, placing phosphoinositide turnover downstream of Draper signalling. Simultaneous Pten knockdown restored phosphoinositide signalling and rescued delayed neuronal clearance in sl-deficient glia. Loss of sl also prevented injury-induced Draper upregulation and disrupted glial calcium signalling responses to axonal injury. In a model of A{beta}42 accumulation, sl knockdown altered brain PIP2/PIP3 balance and improved survival independently of amyloid burden. Together, these findings identify PLC{gamma}-dependent phosphoinositide turnover as a conserved regulator of Draper-mediated glial engulfment and provide mechanistic insight into how PLCG2 influences glial function and neurodegenerative disease risk. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/729572v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@5beb6org.highwire.dtl.DTLVardef@12bc7c5org.highwire.dtl.DTLVardef@1486ba0org.highwire.dtl.DTLVardef@1921395_HPS_FORMAT_FIGEXP M_FIG C_FIG