Bisecting GlcNAc in N-glycan regulates synaptic maturation.

Copine-6 integrates calcium, phosphoinositide and Rab11 signals to coordinate glutamate receptor recycling

Endosomal trafficking is a major pathway that delivers cell-surface proteins, including glutamate receptors, to support neurotransmission and normal brain functions. Activity-dependent insertion of glutamate receptors is essential for synaptic plasticity, learning and memory. Copine-6 is a neuronal-specific calcium (Ca2+) binding protein that mediates activity-induced exocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors. The activation of N-methyl-D-aspartate (NMDA) receptors triggers Ca2+-dependent translocation of Copine-6 to intracellular endosomal compartments. However, the mechanisms underlying the activity-dependent accumulation of Copine-6 in endosomes remain unknown. Here, we show that Copine-6 exhibits Ca2+-dependent binding to phosphatidylinositol-3-phosphate (PI(3)P) through the C2B domain and displays enhanced interaction with active Rab11a in a Ca2+-independent manner via the vWA domain. Mutations in the C2B that inhibit binding to PI(3)P not only block the activity-induced translocation of Copine-6 to early endosomes, but it also causes an aberrant accumulation of Copine-6 in recycling endosomes. Consequently, loss of Copine-6 expression impairs the efficient coupling of early and recycling endosomes and blocks activity-dependent delivery of both AMPA and NMDA receptors onto the neuronal plasma membrane. These defects can be restored by re-expressing wild-type Copine-6, but not the C2B phospholipid-binding mutant. Together, our findings establish Copine-6 as a molecular bridge that enhances coupling between the early and recycling endosomal membranes, thereby facilitating the activity-dependent forward trafficking of glutamate receptors to the neuronal plasma membrane to maintain synaptic potentiation. Significance Statement Activity-dependent trafficking of glutamate receptors is essential for synaptic plasticity, learning, and memory, but the mechanisms coordinating receptor transport through endosomal compartments remain unclear. This study identifies the neuronal calcium-binding protein Copine-6 as a molecular bridge that couples early and recycling endosomes during receptor trafficking. Copine-6 integrates calcium-dependent phospholipid binding and Rab11-mediated endosomal interactions to promote activity-dependent delivery of both AMPA and NMDA receptors to the neuronal surface. Loss of Copine-6 or disruption of its phospholipid-binding activity uncouples endosomal trafficking and impairs receptor insertion during synaptic potentiation. These findings reveal a key mechanism linking neuronal activity, endosomal organization, and glutamate receptor delivery to support synaptic function.

Impacts of N-glycanase1 (NGLY1) Down Regulation on the Function of Mitochondria.

Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1.

Affinity purification-based proteomics shows that Ptn associates with heparan sulfate (HS)-modified neurexin1 (HS-Nrxn1) in the brain through an HS-glycan-dependent mechanism, which establishes Ptn as an extracellular organizer of presynaptic development and support a model in which Nrxn1's HS glycan provides a platform for extracellular ligand recruitment.

Primate-specific regulation of the human glycosphingolipid gatekeeper UGCG

α2-3-sialylated glycosphingolipids in neuroinflammation, immunity, and programmed cell death: mechanistic evidence and context-dependent regulation: a comprehensive review

α2-3-sialylated glycosphingolipids (α2-3-GSLs) are major constituents of neuronal membranes and lipid rafts, where they shape receptor compartmentalization, signal-complex assembly, and cell-cell communication. Their biological effects, however, vary by molecular subtype, cell type, disease stage, concentration, and local microenvironment. This review synthesizes evidence on spatiotemporal alterations in α2-3-GSL profiles and their relationships to neuroinflammation, immune responses, proteostasis, and programmed cell death across Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and Guillain–Barré syndrome. Particular attention is given to GM1, GD1a, and GD3 and to mechanisms involving TLR4/NF-κB, PI3K/AKT, autophagy-lysosomal function, complement, damage-associated molecular patterns (DAMPs) recognition, and death-receptor signaling. Evidence is stratified into relatively well-supported, model-specific or incomplete, and conceptually inferred mechanisms. On this basis, we propose a lipid–inflammation–immunity–cell death framework that organizes potentially shared downstream processes while explicitly retaining disease-specific differences. This framework is not a validated universal causal pathway; rather, it provides an analytical structure for identifying evidence gaps and testable hypotheses. Disease-specific and parallel cross-disease studies, coupled with spatial lipidomics, in vivo tracing, and subtype-selective interventions, will be required to determine when α2-3-GSL manipulation is protective, neutral, or harmful and to support rational clinical translation.

Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation

Highlights What are the main findings? O-GlcNAcylation exerts context-dependent effects in neurodegenerative diseases rather than being uniformly protective or detrimental. We propose a state-resolved framework integrating disease stage, cell type, subcellular localization, substrate specificity, and therapeutic intervention dynamics. What are the implications of the main findings? This framework provides a more precise interpretation of conflicting findings regarding O-GlcNAc modulation across different neurodegenerative disorders. Future therapeutic strategies should focus on correcting disease-relevant O-GlcNAc states rather than on globally increasing or decreasing total O-GlcNAcylation. Abstract O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.