Abstract
Niemann-Pick, type C1 (NPC1) is a fatal, neurodegenerative disease, which belongs to the family of lysosomal diseases. In NPC1, endo/lysosomal accumulation of unesterified cholesterol and sphingolipids arise from improper intracellular trafficking resulting in multi-organ dysfunction. With the proximity between the brain and cerebrospinal fluid (CSF), performing differential proteomics provides a means to shed light to changes occurring in the brain. In this study, CSF samples obtained from NPC1 individuals and unaffected controls were used for protein biomarker identification. A subset of these individuals with NPC1 are being treated with miglustat, a glycosphingolipid synthesis inhibitor. Of the 300 identified proteins, 71 proteins were altered in individuals with NPC1 compared to controls including cathepsin D, and members of the complement family. Included are a report of 10 potential markers for monitoring therapeutic treatment. We observed that pro-neuropeptide Y (NPY) was significantly increased in NPC1 individuals relative to healthy controls; however, individuals treated with miglustat displayed levels comparable to healthy controls. In further investigation, NPY levels in a NPC1 mouse model corroborated our findings. We posit that NPY could be a potential therapeutic target for NPC1 due to its multiple roles in the central nervous system such as attenuating neuroinflammation and reducing excitotoxicity.
| Original language | English (US) |
|---|---|
| Article number | 2200378 |
| Journal | Proteomics |
| Volume | 23 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jun 2023 |
Funding
This work was supported by the intramural research program of the , National Institute of Child Health and Human Development, National Institutes of Health (ZIA GD008989) to Dr Forbes D. Porter and by the National Niemann Pick Disease Foundation Peter Pentchev Fellowship to Stephanie M. Cologna. Additional funding is acknowledged from NIA/NINDS NIH (R01 NS114413), Ara Parseghian Medical Research Fund at Notre Dame, and Together Strong NPC Foundation. The authors acknowledge support from the Department of Chemistry, College of Liberal Arts and Science, University of Illinois Chicago. Scientific input from Dr. Antony Cougnoux and the late Dr. Alfred L. Yergey, III is acknowledged. We would also like to recognize the contribution of the trial participants and their families. Eunice Kennedy Shriver This work was supported by the intramural research program of the Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health (ZIA GD008989) to Dr Forbes D. Porter and by the National Niemann Pick Disease Foundation Peter Pentchev Fellowship to Stephanie M. Cologna. Additional funding is acknowledged from NIA/NINDS NIH (R01 NS114413), Ara Parseghian Medical Research Fund at Notre Dame, and Together Strong NPC Foundation. The authors acknowledge support from the Department of Chemistry, College of Liberal Arts and Science, University of Illinois Chicago. Scientific input from Dr. Antony Cougnoux and the late Dr. Alfred L. Yergey, III is acknowledged. We would also like to recognize the contribution of the trial participants and their families.
Keywords
- NPC1
- NPY
- biomarker
- lysosome
- neurodegeneration
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology