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Peters, O. M.

Publications and source records attributed to Peters, O. M..

2 recordsLinked to original sources
bioRxiv2026

Phosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in glia

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

neuroscience↗
bioRxiv2025

Alzheimer's disease risk gene Wwox protects against amyloid pathology through metabolic reprogramming

Genome wide association studies have identified multiple loci that mediate the risk of developing late-onset Alzheimers Disease (LOAD). The gene WW-domain containing oxidoreductase (WWOX) has been identified in recent LOAD risk meta-analyses, yet its function in the brain is poorly understood. Using Drosophila, we discovered that knockdown of the highly conserved Wwox gene impacts longevity and sleep, having roles in both neuronal and glial subtypes. In an amyloid beta 42 (A{beta}42) transgenic model of AD, RNAi-mediated knockdown of Wwox significantly decreased both lifespan and locomotion whilst elevating soluble A{beta}42. Transcriptomic and metabolomic analyses revealed that these effects were accompanied by elevated lactate dehydrogenase (Ldh) mRNA and lactate levels, downstream of an increase in the key unfolded protein response protein Atf4. Strikingly, we found that upregulation of Wwox in the A{beta}42 model through CRISPR activation significantly reduced amyloid load, improved longevity and locomotion. Multi-omics analysis revealed Wwox upregulation partially reversed several key A{beta}42-induced transcriptional pathways in the brain and reduced levels of L-methionine and associated enzymes. These findings support a role for reduced WWOX levels in the genetic risk of developing LOAD via pyruvate metabolism and point towards WWOX activation as a protective therapeutic strategy.

neuroscience↗