Lipids on Trial: The Search for the Offending Metabolite in Niemann-Pick type C Disease

Abstract

Niemann-Pick disease type C is a complex lysosomal storage disorder caused by mutations in either the NPC1 or NPC2 genes that is characterized at the cellular level by the storage of multiple lipids, defective lysosomal calcium homeostasis and unique trafficking defects. We review the potential role of each of the individual storage lipids in initiating the pathogenic cascade and propose a model of NPC1 and NPC2 function based on the current knowledge

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

“…Larger studies are needed to explore effects of treatment on NPC amyloid metabolism. Such studies might elucidate the links between amyloid metabolism, lipid homeostasis and vesicular trafficking, which are receiving increasing attention in different neurodegenerative diseases, including AD (Grimm et al 2007;HirschReinshagen et al 2009;Lloyd-Evans and Platt 2010). The longitudinal stability of Ab biomarkers suggests low analytical and biological variability of these parameters in NPC, opening for Ab measurements to study biochemical effects from amyloid-targeting drugs in NPC.…”

“…Other patients have mutations in the NPC2 gene that encodes a soluble lysosomal cholesterol-binding protein (Naureckiene et al 2000). These mutations point to a defect in cholesterol transport in NPC, but the lipid accumulation is complex and the primary offending metabolite in the brain is disputed (Lloyd-Evans and Platt 2010).…”

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…Deficiency in NPC1 protein leads to a massive accumulation of cholesterol in visceral organs of the mice. We and others have shown that, at end-stage, hepatic cholesterol levels are 10-fold higher in Npc1 nih mice compared to wt littermates [53,54] (Marques et al unpublished). The extreme sterol accumulation in lysosomes is thought to impair the activity of other lysosomal hydrolases [24,25,55].…”

Altered vitamin E status in Niemann-Pick type C disease

“…Briefl y, 4 pmol purifi ed sterol binding domain somes accumulate large amounts of free cholesterol, intracellular transport of glycosphingolipids, sphingomyelin, and sphingosine is also severely perturbed ( 22 ). Which of these trapped molecules (or their metabolites) is the metabolic root for the NPC pathology is presently unknown ( 22 ).…”