Defective platelet function in Niemann-Pick disease type C1.

Autor: Chen OCW; Department of Pharmacology University of Oxford Oxford UK., Colaco A; Department of Pharmacology University of Oxford Oxford UK., Davis LC; Department of Pharmacology University of Oxford Oxford UK., Kiskin FN; Department of Pharmacology University of Oxford Oxford UK., Farhat NY; 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., Speak AO; Department of Pharmacology University of Oxford Oxford UK., Smith DA; Department of Pharmacology University of Oxford Oxford UK., Morris L; Department of Pharmacology University of Oxford Oxford UK., Eden E; Institute of Ophthalmology-Cell Biology University College London London UK., Tynan P; Department of Pharmacology University of Oxford Oxford UK., Churchill GC; Department of Pharmacology University of Oxford Oxford UK., Galione A; Department of Pharmacology University of Oxford Oxford UK., Porter FD; 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., Platt FM; Department of Pharmacology University of Oxford Oxford UK.
Jazyk: angličtina
Zdroj: JIMD reports [JIMD Rep] 2020 Sep 12; Vol. 56 (1), pp. 46-57. Date of Electronic Publication: 2020 Sep 12 (Print Publication: 2020).
DOI: 10.1002/jmd2.12148
Abstrakt: 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.
Competing Interests: The authors have no conflict of interest.
(© 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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