Phosphoinositides are a family of critical signaling lipids responsible for cellular functions ranging from growth and differentiation to vesicle trafficking. Niemann-Pick Disease, type C1 (NPC1) is an autosomal recessive, neurodegenerative lipid storage disorder characterized by endo/lysosomal accumulation of unesterified cholesterol and glycosphingolipids. In this study we developed a reliable MALDI-MSI method and a series of LC-MS assays to evaluate phosphoinositide levels in control and NPC1 mutant mouse brain tissues. Our data indicates a decrease in multiple phosphoinositides in the cerebellum of NPC1 mutant animals beginning at asymptomatic ages. Most importantly, we were able to find phosphoinositide alterations in NPC1-mutant mouse cerebellar myelin suggesting lipid composition change in myelin with the disease progression. Investigation of the enzymes and transport proteins responsible for phosphoinositide synthesis and metabolism revealed alteration in the 4-alpha kinase. Our current work is focused on further investigation of NPC1 myelin composition and understanding the functional consequences of these alterations as they relate to progressive neurodegeneration.
Koralege C. Pathmasiri1, Melissa R. Pergande1, Fernando Tobias1, Ernesto Bongarzone2 and Stephanie M. Cologna1 1Department of Chemistry, University of Illinois at Chicago, Chicago, IL 2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago
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