Defective platelet function in Niemann‐Pick disease type C1
Oscar C. W. Chen,
Alexandria Colaco,
Lianne C. Davis,
Fedir N. Kiskin,
Nicole Y. Farhat,
Anneliese O. Speak,
David A. Smith,
Lauren Morris,
Emily Eden,
Patricia Tynan,
Grant C. Churchill,
Antony Galione,
Forbes D. Porter,
Frances M. Platt
Affiliations
Oscar C. W. Chen
Department of Pharmacology University of Oxford Oxford UK
Alexandria Colaco
Department of Pharmacology University of Oxford Oxford UK
Lianne C. Davis
Department of Pharmacology University of Oxford Oxford UK
Fedir N. Kiskin
Department of Pharmacology University of Oxford Oxford UK
Nicole Y. Farhat
Division in Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services Bethesda Maryland USA
Anneliese O. Speak
Department of Pharmacology University of Oxford Oxford UK
David A. Smith
Department of Pharmacology University of Oxford Oxford UK
Lauren Morris
Department of Pharmacology University of Oxford Oxford UK
Emily Eden
Institute of Ophthalmology—Cell Biology University College London London UK
Patricia Tynan
Department of Pharmacology University of Oxford Oxford UK
Grant C. Churchill
Department of Pharmacology University of Oxford Oxford UK
Antony Galione
Department of Pharmacology University of Oxford Oxford UK
Forbes D. Porter
Division in Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services Bethesda Maryland USA
Frances M. Platt
Department of Pharmacology University of Oxford Oxford UK
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 (Ca2+) 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 Ca2+ 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 Ca2+ 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 Ca2+ flux in the function of platelet LROs.
