Journal Article

Quantitative Proteomic Analysis of Niemann-Pick Disease, Type C1 Cerebellum Identifies Protein Biomarkers and Provides Pathological Insight

Porter, Forbes D., Yergey, Alfred L., Cluzeau, Celine V. M., Siebel, Stephan, Backlund, Peter S., Dail, Michelle K., Yanjanin, Nicole M., Toth, Cynthia L., Jiang, Xiao-Sheng, Jun, Hyun-sik, Wassif, Christopher A., Cologna, Stephanie M.

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age / Alzheimer Disease - genetics / Alzheimer's disease / Animal models / Animals / Apoptosis / Ataxia / Biology / Biomarkers / Biomarkers - cerebrospinal fluid / Biomarkers - metabolism / Blotting, Western / Brain / Brain diseases / Cerebellum / Cerebellum - metabolism / Cerebellum - pathology / Cerebrospinal fluid / Child / Childrens health / Cholesterol / Clinical trials / Comparative analysis / Cyclin-dependent kinases / Detoxification / Electrophoresis / Electrophoresis, Gel, Two-Dimensional / Endocrinology / Fatty acid-binding protein / Fatty acids / Female / Gangliosides / Gel electrophoresis / Gene expression / Gene Expression Profiling / Genetic aspects / Genetic disorders / Glucose / Glucose metabolism / Glutathione / Glutathione transferase / Humans / Inflammation / Mass spectrometry / Mass Spectrometry - methods / Mass spectroscopy / Medicine / Metabolic disorders / Metabolism / Mice / Mice, Inbred BALB C / Mice, Knockout / Middle Aged / Mutation / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Niemann-Pick disease / Niemann-Pick Disease, Type C - cerebrospinal fluid / Niemann-Pick Disease, Type C - metabolism / Npc1 protein / Oligonucleotide Array Sequence Analysis / Oxidative metabolism / Oxidative stress / Pathophysiology / Patients / Physiological aspects / Pick's disease / Prefrontal Cortex - metabolism / Protein binding / Proteins / Proteins - genetics / Proteins - metabolism / Proteome - analysis / Proteomics - methods / Reverse Transcriptase Polymerase Chain Reaction / Scientific imaging / Superoxide dismutase / Superoxides / Therapy