Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann–Pick Disease Type C

Abstract

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder caused by the mutation of cholesterol-transporting proteins. In addition, early treatment is important for good prognosis of this disease because of the progressive neurodegeneration. However, the diagnosis of this disease is difficult due to a variety of clinical spectrum. Lysosphingomyelin-509, which is one of the most useful biomarkers for NPC, was applied for the rapid and easy detection of NPC. The fact that its chemical structure was unknown until recently implicates the unrevealed pathophysiology and molecular mechanisms of NPC. In this study, we aimed to elucidate the structure of lysosphingomyelin-509 by various mass spectrometric techniques. As our identification strategy, we adopted analytical and organic chemistry approaches to the serum of patients with NPC. Chemical derivatization and hydrogen abstraction dissociation–tandem mass spectrometry were used for the determination of function groups and partial structure, respectively. As a result, we revealed the exact structure of lysosphingomyelin-509 as N-acylated and O-phosphocholine adducted serine. Additionally, we found that a group of metabolites with N-acyl groups were increased considerably in the serum/plasma of patients with NPC as compared to that of other groups using targeted lipidomics analysis. Our techniques were useful for the identification of lysosphingomyelin-509.

Clinical Disease Progression and Biomarkers in Niemann–Pick Disease Type C: A Prospective Cohort Study

“…This study aimed to characterize novel NPC disease biomarkers in order to establish a set of biomarkers for NPC that are focused on interventions targeting the HSP system in NPC and the underlying cellular pathology of NPC, including altered NPC1/2 protein function and lipid metabolism. During the time of this study and its publication, it is worth noting that other biomarkers such as lyso-sphingomyelin-509 and bile acids have also shown potential as biomarkers of NPC disease [41,[48][49][50].…”

Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study 

“…This study aimed to characterize novel NPC disease biomarkers in order to establish a set of biomarkers for NPC that are focused on interventions targeting the HSP system in NPC and the underlying cellular pathology of NPC, including altered NPC1/2 protein function and lipid metabolism. During the time of this study and its publication, it is worth noting that other biomarkers such as lyso-sphingomyelin-509 and bile acids have also shown potential as biomarkers of NPC disease [41,[51][52][53].…”

Identification and Evaluation of Biomarkers for Niemann-Pick Disease Type C Based on Chemical Analysis Techniques

“…In addition, the exact mass, HAD-MS/MS patterns, and derivatization reaction results matched completely. Thus, it was concluded that Lyso-SM-509 was PPCS [108]. From the simultaneous analysis of PPCS and SPC in the serum/plasma of 20 healthy subjects, 15 NPC, 6 other lysosomal disease, and 43 patients suspected for NPC without the NPC1 or NPC2 mutations, the metabolites in the NPC patient samples were significantly higher than the other subjects.…”