Naslov
Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Autori
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.

Izvornik
Nature communications (2041-1723) 12 (2021), 1; 1158, 20

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
lipid trafficking ; microglia ; NPC ; phagocytic impairment ; proteome

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA