1. Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.
- Author
-
Fremuth LE, Hu H, van de Vlekkert D, Annunziata I, Weesner JA, and Alessandra d'Azzo
- Subjects
- Animals, Mice, Syk Kinase metabolism, NF-kappa B metabolism, Humans, Adaptor Proteins, Signal Transducing metabolism, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha metabolism, Chemokine CCL3 metabolism, Proto-Oncogene Proteins c-akt metabolism, N-Acetylneuraminic Acid metabolism, Neuraminidase metabolism, Microglia metabolism, Microglia pathology, Receptors, Immunologic metabolism, Receptors, Immunologic genetics, Membrane Glycoproteins metabolism, Phagocytosis, Signal Transduction
- Abstract
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 examine 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 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is 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) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation., Competing Interests: Declaration of interests I.A. and A.d’A. are named on the patent application “Methods and compositions to detect the level of lysosomal exocytosis activity and methods of use,” no. PCT/US2012/052629, related to the research reported herein., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2025
- Full Text
- View/download PDF