How Neuraminidase 1 regulates neuropathogenesis?
Sialic acids from sialoglycoproteins are cleaved by Neuraminidase 1 (Neu1). Trem2 is a substate of Neu1. Both Neu1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis.
The researchers illuminate a mechanism in which Neu1 regulates microglia cellular state through modulating the sialylation of Trem2.
When Neu1 is absent, Trem2 remains sialylated, resulting in accumulation, enhanced processing into two biologically active fragments, Trem2 C-terminal fragment (Trem2-CTF) and soluble Trem2, and altered or abolished Trem2- dependent signaling.
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.
Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3.
https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01555-9
