TY - JOUR
T1 - A differential proteomics study of cerebrospinal fluid from individuals with Niemann-Pick disease, Type C1
AU - Li, Wenping
AU - Pergande, Melissa R.
AU - Crutchfield, Christopher A.
AU - Searle, Brian C.
AU - Backlund, Peter S.
AU - Picache, Jaqueline A.
AU - Burkert, Kathryn
AU - Yanjanin-Farhat, Nicole M.
AU - Blank, Paul S.
AU - Toth, Cynthia L.
AU - Wassif, Christopher A.
AU - Porter, Forbes D.
AU - Cologna, Stephanie M.
N1 - Publisher Copyright:
© 2022 The Authors. Proteomics published by Wiley-VCH GmbH.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - NPC1
KW - NPY
KW - biomarker
KW - lysosome
KW - neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85147300847&partnerID=8YFLogxK
U2 - 10.1002/pmic.202200378
DO - 10.1002/pmic.202200378
M3 - Article
C2 - 36638187
AN - SCOPUS:85147300847
SN - 1615-9853
VL - 23
JO - Proteomics
JF - Proteomics
IS - 11
M1 - 2200378
ER -