Biology subjects

Maddison, D.

Publications and source records attributed to Maddison, D..

3 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

Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates

The endoplasmic reticulum (ER)s continuous morphology is tightly controlled by ER-shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimers disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub-Hz firing bursts to ER ultrastructural manipulations in hiPSC-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ERs capability to supply repetitive Ca2+ bursts. The ER morpho-regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. These results expose the selective vulnerability of Ca2+-firing cells to ER structural disruptions, rationalising ER dysfunction in neurodegeneration. This mechanism could apply universally to Ca2+-firing cells.

cell biology↗

bioRxiv2019

Opposing modulation of Cx26 gap junctions and hemichannels by CO2

Cx26 hemichannels open in response to moderate elevations of CO2 (PCO2 55 mmHg) via a carbamylation reaction that depends on residues K125 and R104. Here we investigate the action of CO2 on Cx26 gap junctions. Using a dye transfer assay, we found that an elevated PCO2 of 55 mmHg greatly delayed the permeation of a fluorescent glucose analogue (NBDG) between HeLa cells coupled by Cx26 gap junctions. However, the mutations K125R or R104A abolished this effect of CO2. Whole cell recordings demonstrated that elevated CO2 reduced the Cx26 gap junction conductance (median reduction 5.6 nS, 95% confidence interval, 3.2 to 11.9 nS) but had no effect on Cx26K125R or Cx31 gap junctions. CO2 can cause intracellular acidification, but using 30 mM propionate we found that acidification in the absence of a change in PCO2 caused a median reduction in the gap junction conductance of 5.3 nS (2.8 to 8.3 nS). This effect of propionate was unaffected by the K125R mutation (median reduction 7.7 nS, 4.1 to 11.0 nS). pH-dependent and CO2-dependent closure of the gap junction are thus mechanistically independent. Mutations of Cx26 associated with the Keratitis Ichthyosis Deafness syndrome (N14K, A40V and A88V) also abolished the CO2-dependent gap junction closure. Elastic network modelling suggests that the lowest entropy state when CO2 is bound, is the closed configuration for the gap junction but the open state for the hemichannel. The opposing actions of CO2 on Cx26 gap junctions and hemichannels thus depend on the same residues and presumed carbamylation reaction.

cell biology↗