Proteomic analysis of mouse models of Niemann-Pick C disease reveals alterations in the steady-state levels of lysosomal proteins within the brain.
Niemann-Pick C disease (NPC) is a neurodegenerative lysosomal disorder characterized by storage of cholesterol and other lipids caused by defects in NPC1, a transmembrane protein involved in cholesterol export from the lysosome, or NPC2, an intralysosomal cholesterol transport protein. Alterations in lysosomal activities have been implicated in NPC pathogenesis therefore the aim of this study was to conduct a proteomic analysis of lysosomal proteins in mice deficient in either NPC1 or NPC2 to identify secondary changes that might be associated with disease. Lysosomal proteins containing the specific mannose 6-phosphate modification were purified from wild-type and Npc1(-/-)  and Npc2(-/-)  mutant mouse brains at different stages of disease progression and identified by bottom-up LC-MS/MS and quantified by spectral counting. Levels of a number of lysosomal proteins involved in lipid catabolism including prosaposin and the two subunits of β-hexosaminidase were increased in both forms of NPC, possibly representing a compensatory cellular response to the accumulation of glycosphingolipids. Several other lysosomal proteins were significantly altered, including proteases and glycosidases. Changes in lysosomal protein levels corresponded with similar alterations in activities and transcript levels. Understanding the rationale for such changes may provide insights into the pathophysiology of NPC.
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA. sleat@cabm.rutgers.edu
David E
DE
Sleat
Jennifer A
JA
Wiseman
Istvan
I
Sohar
Mukarram
M
El-Banna
Haiyan
H
Zheng
Dirk F
DF
Moore
Peter
P
Lobel
D000818:Animals; D001921:Brain / Q000378:metabolism*; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D053719:Tandem Mass Spectrometry; D059467:Transcriptome; D033921:Vesicular Transport Proteins / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins; C018589:lysosomal proteins