Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by
liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of
cholesterol and
glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential
biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice.
Biological pathways showing early altered gene expression included: lipid metabolism,
cytochrome P450 enzymes involved in
arachidonic acid and
drug metabolism,
inflammation and immune responses,
mitogen-activated protein kinase and
G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late
pathological processes. To identify potential
biomarkers that could facilitate monitoring of
disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted
proteins. Further analysis identified two secreted
proteins with increased serum levels in NPC1 patients:
galectin-3 (
LGALS3), a pro-inflammatory molecule, and
cathepsin D (CTSD), a lysosomal aspartic
protease. Elevated serum levels of both
proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of
Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a
therapy that reduces pathological findings and significantly increases Npc1(-/-) survival. Both
LGALS3 and CTSD have the potential to aid in diagnosis and serve as
biomarkers to monitor efficacy in therapeutic trials.