Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

• DOI: 10.1074/mcp.m114.045609
• Publication Date: 2015-04-15T01:52:46Z
• Authors: Navin Rauniyar; Kanagaraj Subrama...; Mathieu Lavallée-...; Salvador Martínez...; William E. Balch; John R. Yates
• Keywords: NPC1; Pathogenesis; Niemann–Pick disease

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in late endosomal/lysosomal compartments. Mutations NPC1 protein are implicated 95% patients with NPC disease. The most prevalent mutation missense I1061T that occurs ∼ 15-20% alleles. In our study, an isobaric labeling-based quantitative analysis proteome NPC1(I1061T) primary fibroblasts when compared wild-type cells identified 281 differentially expressed proteins based on stringent data criteria. Gene ontology enrichment revealed these play important roles diverse cellular processes such as maturation, energy metabolism, metabolism reactive oxygen species, antioxidant activity, steroid lipid localization, and apoptosis. relative expression level subset (TOR4A, DHCR24, CLGN, SOD2, CHORDC1, HSPB7, GAA) was independently successfully substantiated Western blotting. We observed treating four classes seven different compounds potential drugs increased SOD2 DHCR24. have also shown abnormal glycogen possibly triggered defective processing lysosomal alpha-glucosidase. Our study provides starting point for future more focused investigations to better understand mechanisms which reported dysregulated triggers pathological cascade NPC, furthermore, their effect upon therapeutic interventions.