Defective platelet function in Niemann‐Pick disease type C1

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.

A differential proteomics study of cerebrospinal fluid from individuals with Niemann‐Pick disease, Type C1

“…Notably, AT III, a thrombin inhibitor that inhibits coagulation of the blood [30], was upregulated (p < 0.00052, Log 2 FC = 0.17) in individuals with NPC1 in the current study (Figure 2, Table S3). Together, the current data is consistent with the notion of impaired blood clotting that was observed in the Npc1 −/− mouse [51].…”

“…In the current study, all three polypeptide chains of fibrinogen (i.e., FGA, FGB, FGG) were detected and found to be decreased in the CSF of individuals with NPC1 compared to controls (Figure 2, Table S3). Consistently, the defective platelet function in the blood of Npc1 −/− mice with impaired thrombin-stimulated platelet aggregation and prolonged bleeding time was reported in a recent study [51].…”

“…Although there is no direct correlation of fibrinogen levels between blood and CSF [52], downregulated fibrinogen in CSF indicates that fibrinogen may also be reduced in the blood since impaired blood clotting has been reported in Npc1 −/− mouse model [51]. Notably, AT III, a thrombin inhibitor that inhibits coagulation of the blood [30], was upregulated (p < 0.00052, Log 2 FC = 0.17) in individuals with NPC1 in the current study (Figure 2, Table S3).…”

Severe neurometabolic phenotype innpc1-/-zebrafish with a C-terminal mutation

“…NPC neurodegeneration also undergoes cytoskeletal pathology, which has been reported in some murine models of NPC (Bu et al, 2002; Zhang et al, 2004) and cytoskeleton alteration was also previously described in a npc1 morphant zebrafish model (Schwend et al, 2011). Some previous studies found collagen reduction in some NPC patients as well as in zebrafish and mouse animal models (Louwette et al, 2013; Chen et al, 2020). Moreover, NPC1 has been demonstrated to have a role in hematopoiesis, with some NPC patients showing hematological defects such as thrombocytopenia, anemia and petechial rash and it was also observed in npc1 zebrafish morphants (Louwette et al, 2013), and angiogenesis has proved to be inhibited by alteration in cholesterol trafficking in NPC individuals (Lyu et al, 2018).…”

“…Mouse models of NPC reproduce some of the main pathological disease features, such as hepatosplenomegaly and loss of cerebellar Purkinje neurons and have been used to test drug compounds for therapy (Chen et al, 2020; Maue et al, 2012; Praggastis et al, 2015; Rodriguez-Gil et al, 2020). Due to its biological features and easy genetic manipulation, Zebrafish is commonly used as a model organism in neuronal (Bandmann and Burton, 2010; Quelle-Regaldie et al, 2021a; Quelle-Regaldie et al, 2021b) and metabolic diseases (Hölttä-Vuori et al, 2010; Ka and Jin, 2021).…”