Quantitative, label-free proteomics in the symptomatic Niemann-Pick, type C1 mouse model using standard flow liquid chromatography and thermal focusing electrospray ionization.

Niemann-Pick Disease, type C1 (NPC1) is a fatal, autosomal recessive, neurodegenerative disorder caused by mutations in the NPC1 gene. As a result, there is accumulation of unesterified cholesterol and sphingolipids in the late endosomal/lysosomal system. This abnormal accumulation results in a cascade of pathophysiological events including progressive, cerebellar neurodegeneration, among others. While significant progress has been made to better understand NPC1, the downstream effects of cholesterol storage and the major mechanisms that drive neurodegeneration remain unclear. In the current study, we (i) implemented the use of a commercial, highly efficient standard flow-ESI platform for protein biomarker identification and (ii) identified and evaluated protein biomarkers at a terminal time point in the NPC1 null mouse model. In this study, we observed alterations in proteins related to fatty acid homeostasis, calcium binding and regulation, lysosomal regulation, inositol biosynthesis and metabolism as well as signaling by Rho family GTPases. New observations from this study include altered expression of Pcp2 and Limp2 in Npc1 mutant mice relative to control, with Pcp2 exhibiting multiple isoforms and specific to the cerebella. This study provides valuable insight to pathways altered in the late-stage pathophysiology of NPC1. This article is protected by copyright. All rights reserved.