Biology subjects

Sockanathan, S.

Publications and source records attributed to Sockanathan, S..

3 recordsLinked to original sources

bioRxiv2026

Region-dependent regulatioin of Tau phosphorylation in a mouse model of tauopathy

Hyperphosphorylation of Tau promotes its aggregation and neurofibrillary tangle (NFT) formation, contributing to neuronal dysfunction and neurodegeneration in diseases such as Alzheimer's Disease (AD) and AD-related dementias (ADRDs). However, the mechanisms underlying dysregulated Tau phosphorylation under pathological contexts remain unclear. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers a subclass of proteins to the membrane. Here, we show that in the PS19 tauopathy mouse model, GDE2 disruption modulates Tau phosphorylation, decreasing Tau's propensity for aggregation by regulating local kinase environments in a region-specific manner. In the cortex, GDE2 ablation in PS19 mice (PS19;Gde2KO) transiently delays Tau phosphorylation at pro-aggregation sites (Serine (S)202/Threonine (T)205, T212, and S396) and accelerates phosphorylation at the anti-aggregation site S262, with a marked reduction in S202/T205 and T212 phosphorylation at 6 months. While Tau phosphorylation at S202/T205 is similarly delayed in the hippocampus, PS19;Gde2KO animals show increased phosphorylation at S262 at 6 months. Consistent with these changes, AKT and Glycogen Synthase Kinase-3 / {beta} (GSK3 / {beta}) activities are decreased in the cortex, while AKT activity is increased in the hippocampus, with no changes in protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activity. Primary cortical neurons from PS19;Gde2KO animals showed reduced Tau phosphorylation at S202/T205, implying cell-autonomous roles for neuronal GDE2 in this process. GDE2 overexpression in heterologous SH-SY5Y cells increased Tau phosphorylation at S202/T205, while a catalytically inactive form of GDE2 did not, suggesting that GDE2 regulation of target GPI-anchored protein surface activity is required to modulate Tau phosphorylation. Taken together, our study identifies GDE2 as a component of the complex regulatory network that controls Tau phosphorylation in the context of tauopathy and provides insight into putative pathways relevant to Tau pathologies observed in disease.

neuroscience↗

bioRxiv2025

Regulation of Glypican 6-mediated Wnt activation maintains TDP-43 nuclear localization in neurons

Abnormalities in TDP-43 (Transactive response DNA-binding protein 43kDa) localization and function span multiple neurodegenerative diseases and are implicated in driving neuronal degeneration and loss. Nuclear pore complex (NPC) abnormalities and disrupted nucleocytoplasmic trafficking (NCT) contribute to TDP-43 mislocalization, but how these cellular changes are initiated in disease is unclear. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a surface glycosylphosphatidylinositol (GPI)-anchor cleaving enzyme that encodes a physiological pathway that ensures NPC integrity, appropriate NCT, and nuclear TDP-43 expression and function in adult neurons by negatively regulating canonical Wnt signaling. Notably, studies of human postmortem tissue and patient-derived neuronal models suggest that the failure of GDE2-dependent regulation of Wnt contributes to TDP-43 abnormalities in disease. Here we show that GDE2 inhibits persistent neuronal Wnt activation by regulating the surface expression of the GPI-anchored protein, Glypican-(GPC)6. Excessive GPC6 surface expression potentiates neuronal Wnt activation in vivo, resulting in NPC disruption, alterations in Ran-dependent NCT, and TDP-43 mislocalization, while genetic reduction of GPC6 in mice lacking GDE2 rescues these cellular abnormalities. Thus, GDE2, GPC6, and the canonical Wnt pathway form a physiologically important signaling axis important for NPC integrity, appropriate NCT, and TDP-43 nuclear function in neurons that, when disrupted, may underlie associated neuropathologies in disease.

neuroscience↗

bioRxiv2019

Epithelial retinoid acid receptor β regulates serum amyloid A expression and vitamin A-dependent intestinal immunity

Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor retinoic acid receptor {beta} (RAR{beta}) is essential for vitamin A-dependent intestinal immunity. Epithelial RAR{beta} activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RAR{beta} promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RAR{beta} was required for the development of key vitamin A-dependent adaptive immune responses, including CD4+ T cell homing to the intestine and the development of immunoglobulin A-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity and highlight the role of epithelial cells in regulating intestinal immunity in response to diet. Significance StatementVitamin A is a nutrient that is essential for the development of intestinal immunity. It is absorbed by gut epithelial cells which convert it to retinol and retinoic acid. Here we show that the transcription factor retinoic acid receptor {beta} (RAR{beta}) allows epithelial cells to sense vitamin A in the diet and regulate vitamin A-dependent immunity in the intestine. We find that epithelial RAR{beta} regulates several intestinal immune responses, including production of the immunomodulatory protein serum amyloid A, T cell homing to the intestine, and B cell production of immunoglobulin A. Our findings provide new insight into how epithelial cells sense vitamin A to regulate intestinal immunity and highlight why vitamin A is so important for immunity to infection.

immunology↗