期刊
JOURNAL OF LIPID RESEARCH
卷 60, 期 8, 页码 1410-1424出版社
ELSEVIER
DOI: 10.1194/jlr.RA119000157
关键词
Niemann-Pick disease type C; mass spectrometry; structural identification; lysoSM-509
资金
- National Institutes of Health Clinical and Translational Science Award [UL1 TR000448, R01 NS081985, P41-GM103422, 2R01DK067859]
- University of Pennsylvania Orphan Disease Center
- Dana's Angels Research Trust
- Ara Parseghian Medical Research Foundation
- Hope for Hayley and Samantha's Search for the Cure Funds
- Referral Center for Animal Models of Human Genetic Disease (National Institutes of Health) [P40 OD010939]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Bench to Bedside Award from the Office of Rare Diseases
- National Institutes of Health Grant [P30 DK020579]
Niemann-Pick disease type C1 (NPC1) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, there is an urgency to improve diagnostics and monitor therapeutic efficacy with biomarkers. In this study, we sought to define the structure of an unknown lipid biomarker for NPC1 with [M + H](+) ion at m/z 509.3351, previously designated as lysoSM-509. The structure of N-palmitoyl-O-phosphocholineserine (PPCS) was proposed for the lipid biomarker based on the results from mass spectrometric analyses and chemical derivatizations. As no commercial standard is available, authentic PPCS was chemically synthesized, and the structure was confirmed by comparison of endogenous and synthetic compounds as well as their derivatives using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPCS is the most abundant species among N-acyl-O-phosphocholineserines (APCS), a class of lipids that have not been previously detected in biological samples. Further analysis demonstrated that all APCS species with acyl groups ranging from C14 to C24 were elevated in NPC1 plasma. PPCS is also elevated in both central and peripheral tissues of the NPC1 cat model. Identification of APCS structures provide an opportunity for broader exploration of the roles of these novel lipids in NPC1 disease pathology and diagnosis.
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