Open AccessDefective platelet function in Niemann‐Pick disease type C1
Author(s) -
Chen Oscar C. W.,
Colaco Alexandria,
Davis Lianne C.,
Kiskin Fedir N.,
Farhat Nicole Y.,
Speak Anneliese O.,
Smith David A.,
Morris Lauren,
Eden Emily,
Tynan Patricia,
Churchill Grant C.,
Galione Antony,
Porter Forbes D.,
Platt Frances M.
Publication year - 2020
Publication title -
jimd reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.412
H-Index - 25
ISSN - 2192-8312
DOI - 10.1002/jmd2.12148
Subject(s) - function (biology) , microbiology and biotechnology , biology
Abstract Niemann‐Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2 . Reduced late endosome/lysosome calcium (Ca 2+ ) levels and the accumulation of unesterified cholesterol and sphingolipids within the late endocytic system characterize this disease. We previously reported impaired lysosome‐related organelle (LRO) function in Npc1 −/− Natural Killer cells; however, the potential contribution of impaired acid compartment Ca 2+ flux and LRO function in other cell types has not been determined. Here, we investigated LRO function in NPC1 disease platelets. We found elevated numbers of circulating platelets, impaired platelet aggregation and prolonged bleeding times in a murine model of NPC1 disease. Electron microscopy revealed abnormal ultrastructure in murine platelets, consistent with that seen in a U18666A (pharmacological inhibitor of NPC1) treated megakaryocyte cell line (MEG‐01) exhibiting lipid storage and acidic compartment Ca 2+ flux defects. Furthermore, platelets from NPC1 patients across different ages were found to cluster at the lower end of the normal range when platelet numbers were measured and had platelet volumes that were clustered at the top of the normal range. Taken together, these findings highlight the role of acid compartment Ca 2+ flux in the function of platelet LROs.