Niemann Pick disease, type C (NPC) is a fatal, autosomal recessive, lysosomal storage disorder that is characterized by progressive cerebellar neurodegeneration. NPC is caused by mutations in either the <i>NPC1</i> or <i>NPC2</i> genes which result in their respective protein dysfunction and inability to traffic cholesterol through the lysosome. The dysfunction of NPC proteins not only affect cholesterol, but numerous other lipids as well. For instance, bioactive sphingolipids, such as gangliosides and ceramides, are altered in NPC and show distinctive spatial distributions in the mouse cerebellum. Currently there is no FDA-approved therapy for NPC disease. However, 2-hydroxypropyl-beta-cyclodextrin (HPβCD) and gene therapy strategies are being explored. In this study, we are investigating changes in sphingolipids and ceramides upon administration of these experimental therapeutics. MALDI mass spectrometry imaging analysis of animals treated with HPβCD revealed a reduction of ceramide accumulation in the mutant brain, as opposed to no change in treated wild type mice This effect was most striking in the cerebellum. Similar results were seen with gangliosides, GM2 and GM3, in the NPC1 brain. Parallel analyses are underway for mice treated with gene therapy.

Mass spectrometry imaging of lipids in Niemann-Pick disease, type C mice treated with experimental therapeutics

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ACS Fall 2022

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