Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease.

André R A Marques,Jan Aten,Cindy P A A Van Roomen,Roelof Ottenhoff,Pilar Giraldo,Tanit L Gabriel,Pilar Alfonso,Nike Claessen,Johannes M F G Aerts,Marco Van Eijk,Pilar Irún

doi:10.1371/journal.pone.0147208

Abstract

Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.

Highlights

Niemann-Pick type C (NPC) disease is an autosomal recessive neurovisceral lysosomal storage disorder (LSD) with an estimated minimal incidence of 1/120 000 live births [1]
Since hepatosplenomegaly is an early indicator of NPC, we focused our analysis on liver and spleen
We report on the possible use of plasma levels of Glycoprotein nonmetastatic melanoma protein B (Gpnmb) as marker for the lysosomal storage disorder NPC

Summary

Introduction

Niemann-Pick type C (NPC) disease is an autosomal recessive neurovisceral lysosomal storage disorder (LSD) with an estimated minimal incidence of 1/120 000 live births [1]. Loss-of-function mutations in the transmembrane protein NPC1 account for approximately 95% of the NPC cases, with the remainder involving the soluble protein NPC2 [2]. NPC1 and NPC2 are thought to function cooperatively in the transport of cholesterol from late endosomal/lysosomal (LE/L) compartment to other cellular sites [3]. Malfunction of either protein leads to the accumulation of unesterified cholesterol in LE/L. Glycosphingolipid (GSL) accumulation occurs, most likely as a result of impaired activity of multiple lysosomal hydrolases [4,5,6].

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