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1.
bioRxiv ; 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38826426

RESUMEN

Neuraminidase 1 (Neu1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, Neu1 regulates immune cells, primarily those of the monocytic lineage. Here we examined how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 was deficient/downregulated, Trem2-FL remained sialylated, accumulated intracellularly, and was excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) did not hinder Trem2-FL-DAP12-Syk complex assembly but impaired signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampened NFκB signaling, while sTrem2 propagated Akt-dependent cell survival and NFAT1-mediated production of TNFα and CCL3. Because Neu1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease (AD) and sialidosis, modulating Neu1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

2.
Cell Rep ; 43(5): 114117, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38630590

RESUMEN

Endoplasmic reticulum-plasma membrane (ER-PM) junctions mediate Ca2+ flux across neuronal membranes. The properties of these membrane contact sites are defined by their lipid content, but little attention has been given to glycosphingolipids (GSLs). Here, we show that GM1-ganglioside, an abundant GSL in neuronal membranes, is integral to ER-PM junctions; it interacts with synaptic proteins/receptors and regulates Ca2+ signaling. In a model of the neurodegenerative lysosomal storage disease, GM1-gangliosidosis, pathogenic accumulation of GM1 at ER-PM junctions due to ß-galactosidase deficiency drastically alters neuronal Ca2+ homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated N-methyl D-aspartate receptor (NMDAR) Ca2+ channel, thereby increasing Ca2+ flux, activating extracellular signal-regulated kinase (ERK) signaling, and increasing the number of synaptic spines without increasing synaptic connectivity. Thus, GM1 clustering at ER-PM junctions alters synaptic plasticity and worsens the generalized neuronal cell death characteristic of GM1-gangliosidosis.


Asunto(s)
Señalización del Calcio , Retículo Endoplásmico , Gangliósido G(M1) , Gangliosidosis GM1 , Receptores de N-Metil-D-Aspartato , Animales , Humanos , Ratones , Calcio/metabolismo , Membrana Celular/metabolismo , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Retículo Endoplásmico/metabolismo , Gangliósido G(M1)/metabolismo , Gangliosidosis GM1/metabolismo , Gangliosidosis GM1/patología , Plasticidad Neuronal , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Masculino , Femenino
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