Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia (CROSBI ID 304821)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Colombo, A ; Dinkel, L. ; Müller, S. A. ; Sebastian Monasor, L. ; Schifferer, M. ; Cantuti-Castelvetri, L. ; König, J. ; Vidatić, Lea ; Bremova-Ertl, T. ; Lieberman, A. ; Hećimović, Silva ; Simons, M. ; Lichtenthaler, S. F. ; Strupp, M. ; Schneider, S. A. ; Tahirović, S.
engleski
Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1−/− microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.
lipid trafficking ; microglia ; NPC ; phagocytic impairment ; proteome
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Povezanost rada
Temeljne medicinske znanosti