Proteomics of the corpus callosum to identify novel factors involved in hypomyelinated Niemann-Pick Type C disease mice

Fan Yang,Yudong Guan,Hartmut Schlüter,Jiankai Luo,Xiao Feng,Arndt Rolfs

doi:10.1186/s13041-019-0440-9

Fan Yang, Yudong Guan + Show 4 more

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https://doi.org/10.1186/s13041-019-0440-9

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Hypomyelination in the central nerves system (CNS) is one of the most obviously pathological features in Niemann-Pick Type C disease (NPC), which is a rare neurodegenerative disorder caused by mutations in the NPC intracellular cholesterol transporter 1 or 2 (Npc1 or Npc2). Npc1 plays key roles in both neurons and oligodendrocytes during myelination, however, the linkage between the disturbed cholesterol transport and inhibited myelination is unrevealed. In this study, mass spectrometry (MS)-based differential quantitative proteomics was applied to compare protein composition in the corpus callosum between wild type (WT) and NPC mice. In total, 3009 proteins from both samples were identified, including myelin structural proteins, neuronal proteins, and astrocyte-specific proteins. In line to hypomyelination, our data revealed downregulation of myelin structural and indispensable proteins in Npc1 mutant mice. Notably, the reduced ceramide synthase 2 (Cers2), UDP glycosyltransferase 8 (Ugt8), and glycolipid transfer protein (Gltp) indicate the altered sphingolipid metabolism in the disease and the involvement of Gltp in myelination. The identification of most reported myelin structural proteins and proteins from other cell types advocates the use of the corpus callosum to investigate proteins in different cell types that regulate myelination.

Highlights

Mutations of either NPC intracellular cholesterol transporter 1 or 2 (Npc1 or NPC intracellular cholesterol transporter 2 (Npc2)) cause the Niemann-Pick Type C disease (NPC), which is a rare recessive neurological disorder [1, 2]
Similar proteomic patterns in the corpora callosa between wild type (WT) and NPC mice To unravel factors that are involved in hypomyelination in NPC disease, three replicates of corpora callosa from either WT or NPC mice at P12 were separated for NanoLC-mass spectrometry (MS)/MS analysis (Fig. 1a-c)
The proteins detected in both WT and NPC mice were used for analysis (Additional file 1: Table S1)

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Introduction

Mutations of either NPC intracellular cholesterol transporter 1 or 2 (Npc or Npc2) cause the Niemann-Pick Type C disease (NPC), which is a rare recessive neurological disorder [1, 2]. The NPC mouse (BALB/cNctr-Npc1m1N/J), carrying a spontaneous mutation of npc without functional Npc protein, is frequently used as the mouse model for NPC disease. Myelin disturbance has been reported in NPC mice in the 1980s [8]. Takikita et al have described hypomyelination in the brain of NPC mice and proposed that disturbed myelination contributes to the axonal injury [6]. Our previous study confirms a delayed and reduced myelination in the corpus callosum of NPC mice with an unaltered number of oligodendrocytes, but their maturation is inhibited [10]

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