Mass spectrometry imaging and LC–MS reveal decreased cerebellar phosphoinositides in Niemann–Pick type C1–null mice

Koralege C. Pathmasiri, Melissa R. Pergande, Fernando Tobias, Rima Rebiai, Avia Rosenhouse-Dantsker, Ernesto R. Bongarzone, Stephanie M. Cologna

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Niemann-Pick disease, type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the NPC1 gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Here, we utilized consensus spectra analysis of MS imaging datasets and orthogonal LC–MS analyses to evaluate the spatial distribution of phosphoinositides and quantify them in cerebellar tissue from Npc1-null mice. Our results suggest significant depletion of multiple phosphoinositide species, including phosphatidylinositol (PI), phosphatidylinositol monophosphate (PIP), and bisphosphate (PIP2), in the cerebellum of the Npc1-null mice in both whole-tissue lysates and myelin-enriched fractions. Additionally, we observed altered levels of the regulatory enzyme phosphatidylinositol 4-NLQDVH W\SH 2 α (PI4K2A) in Npc1-null mice. In contrast, the levels of related kinases, phosphatases, and transfer proteins were unaltered in the Npc1-null mouse model as observed by Western blot analysis. Our discovery of phosphoinositide lipid biomarkers for NPC1 opens new perspectives on the pathophysiology underlying this fatal neurodegenerative disease.

Original languageEnglish
Pages (from-to)1004-1013
Number of pages10
JournalJournal of Lipid Research
Issue number7
StatePublished - Jul 2020
Externally publishedYes


  • Bisphosphate (PIP)
  • Cholesterol
  • Genetic metabolic disorder
  • Lysosomal storage disorder
  • Mass spectrometry imaging
  • Neurodegeneration
  • Niemann-Pick disease type C (NPC)
  • Phosphoinositide signaling
  • Phospholipid
  • Signal transduction


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