title: Quantitative proteomic analysis of Niemann-Pick disease, type C1 cerebellum identifies protein biomarkers and provides pathological insight.
abstract: Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase α, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials.
authors.affiliation: Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cologna
authors.forename: Xiao-Sheng
authors.initials: XS
authors.lastname: Jiang
authors.forename: Peter S
authors.initials: PS
authors.lastname: Backlund
authors.forename: Celine V M
authors.initials: CV
authors.lastname: Cluzeau
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Dail
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Yanjanin
authors.forename: Stephan
authors.initials: S
authors.lastname: Siebel
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Toth
authors.forename: Hyun-sik
authors.initials: HS
authors.lastname: Jun
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Yergey
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism*; D015153:Blotting, Western; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D002648:Child; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000134:cerebrospinal fluid / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D040901:Proteomics / Q000379:methods*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D020543:Proteome