title: Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1.
abstract: 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.
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Celine V M
authors.initials: CV
authors.lastname: Cluzeau
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Watkins-Chow
authors.forename: Rao
authors.initials: R
authors.lastname: Fu
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Borate
authors.forename: Nicole
authors.initials: N
authors.lastname: Yanjanin
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Dail
authors.forename: Cristin D
authors.initials: CD
authors.lastname: Davidson
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000293:Adolescent; D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D002402:Cathepsin D / Q000097:blood* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D037502:Galectin 3 / Q000097:blood* / Q000235:genetics; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D059467:Transcriptome; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D037502:Galectin 3; D047908:Intracellular Signaling Peptides and Proteins; C485095:Lgals3 protein, mouse; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003577:Cytochrome P-450 Enzyme System; D002402:Cathepsin D; C533923:Ctsd protein, mouse