Complex lipid trafficking in Niemann‐Pick disease type C

Abstract

Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…These two proteins are involved in the egress of cholesterol from late endosomal/lysosomal (LE/LY) compartments. In NPC patients, principally young children, cholesterol accumulates within cells causing multiorgan failures (liver, lungs), neurodegeneration, seizures, impaired cognition and motor functions leading to early patient death [105]. The discovery of the genes involved in the human pathogenesis, as well as animal models harboring spontaneous mutations or induced mutation in Npc genes, greatly contributed to advances in understanding NPC development [106][107][108].…”

The Spectrum of Niemann-Pick Type C Disease in Greece

“…On the other hand, the NPC2 gene (MIM ID: 601015) encodes a small (151 amino acids) soluble lysosomal protein (Naureckiene et al 2000;Vanier and Millat 2004). Both the NPC1 and the NPC2 proteins are required for the egress of endocytosed cholesterol from late endosomes/lysosomes (Vance and Karten 2014;Vanier 2015). Up to date more than 400 and 20 mutations have been reported in the NPC1 and NPC2 genes, respectively (HGMD professional 2016.2).…”

Reversal of Pathologic Lipid Accumulation in NPC1-Deficient Neurons by Drug-Promoted Release of LAMP1-Coated Lamellar Inclusions

“…In most cases, it is unknown where the macromolecular complexes form, how they damage neurons, and whether they can be dissolved. We have addressed these key questions in Niemann-Pick type C (NPC) disease (OMIM #257220), a rare and ultimately fatal autosomal recessive lysosomal storage disorder with aggravating neurologic symptoms (Vance and Karten, 2014;Vanier, 2015) due to progressive neurodegeneration in specific brain areas (Tanaka et al, 1988;German et al, 2001;Yamada et al, 2001;Luan et al, 2008). The disease is caused by genetic defects in NPC1 or NPC2, which are located in the membrane and lumen of late endosomes, respectively (Loftus et al, 1997;Naureckiene et al, 2000).…”

“…The dysfunction of NPC1 or NPC2 causes accumulation of unesterified cholesterol in the endosomal-lysosomal system (Sokol et al, 1988;Liscum et al, 1989;Kobayashi et al, 1999), which can be detected by cytochemical staining with the fluorescent polyene filipin (Gimpl, 2010). The presence of filipin-positive "perinuclear vesicles" in patient-derived fibroblasts has served as a key diagnostic indicator of NPC disease (Vanier, 2015).…”