Concurrent increase of cholesterol, sphingomyelin and glucosylceramide in the spleen from non‐neurologic Niemann–Pick type C patients but also patients possibly affected with other lipid trafficking disorders

Abstract

Niemann^Pick type C disease (NPC) is a neurovisceral (or, extremely rarely, only visceral) lipidosis caused by mutations in the NPC1 gene or, in a few patients, the HE1 gene, which encode sterol regulating proteins. NPC is characterised by a complex lipid anomaly including a disturbed cellular tra⁄cking of cholesterol but also multi-lipid storage in visceral organs and brain. Lipids were studied using conventional methods in enlarged spleens that had been removed from ¢ve patients for di¡erent therapeutic and diagnostic reasons and found to have microscopic signs of lysosomal storage disease not suspected clinically. The spleen lipid ¢ndings with a concurrent accumulation of cholesterol, sphingomyelin and glucosylceramide (Acc-CSG) allowed us to suggest NPC diagnoses for these patients, who were free of neurologic symptoms. From two patients no material for con¢rmatory studies was available, but in two other patients NPC diagnoses could be con¢rmed with the ¢lipin cytochemical cholesterol assay and NPC1 gene analysis, respectively. However, these tests and also HE1 gene analysis were negative in a third patient. Since the Acc-CSG lipid pattern seems to indicate a multi-lipid tra⁄cking defect rather than being highly speci¢c for NPC, this patient, if not a¡ected with very atypical NPC, may be a candidate for a di¡erent lipid tra⁄cking disorder. The Acc-CSG pattern was considered to be similar to the lipid pattern known for the lipid rafts, these functional cell structures being probably disorganised and accumulated in late endosomes and lysosomes of NPC cells. ß

Acid sphingomyelinase activity is regulated by membrane lipids and facilitates cholesterol transfer by NPC2

“…A plausible cause for the lysosomal SM accumulation might be the reduced ASM activity observed in cells and organs of NPC1-deficient patients and mice (58, 67–70). ASM activity might be reduced by proteolytic degradation of ASM protein: accumulating cationic sphingosine in NPC disease may trigger ASM degradation, as observed by cationic desipramine in cell cultures (25, 26).…”

Sphingomyelins suppress the targeted disruption of lysosomes/endosomes by the photosensitizer NPe6 during photodynamic therapy

“…The present study also raises the issue of whether modulation of sphingolipid content/type can influence susceptibility to specific classes of apoptotic inducers. This question may be particularly germane to diseases with perturbations of SM/cholesterol contents, such as lysosomal storage diseases [52][53][54].…”

Improvement in Lipid and Protein Trafficking in Niemann-Pick C1 Cells by Correction of a Secondary Enzyme Defect

“…It remains unclear whether the primary defect in NPC1 mutants is directly associated with cholesterol transport or whether the cholesterol accumulation is secondary to accumulation of other lipids, which associate with cholesterol in membranes (4,10). In this regard, it is noteworthy that cholesterol-enriched NPC cells and tissues from NPC1-mutant mice and humans have a secondary, post-translational defect in the activity of a lysosomal enzyme, acid sphingomyelinase (SMase) (14-19). This alteration in acid SMase activity can be observed in wild-type (WT) cells with increased levels of late endosomal cholesterol resulting from incubation with low-density lipoprotein (LDL) and progesterone (16).…”