Chen, OCW;
Colaco, A;
Davis, LC;
Kiskin, FN;
Farhat, NY;
Speak, AO;
Smith, DA;
... Platt, FM; + view all
(2020)
Defective platelet function in Niemann-Pick disease type C1.
JIMD Reports
, 56
(1)
pp. 46-57.
10.1002/jmd2.12148.
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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.
| Type: | Article |
|---|---|
| Title: | Defective platelet function in Niemann-Pick disease type C1 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/jmd2.12148 |
| Publisher version: | http://dx.doi.org/10.1002/jmd2.12148 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM. |
| Keywords: | calcium (Ca2+), lysosome, lysosome‐related organelle, Niemann‐Pick disease type C |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10115848 |
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