Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease.
Niemann-Pick type C1 (NPC1) disease is a rare progressive neurodegenerative disorder characterized by accumulation of cholesterol in the endolysosomes. Previous studies implicating oxidative stress in NPC1 disease pathogenesis raised the possibility that nonenzymatic formation of cholesterol oxidation products could serve as disease biomarkers. We measured these metabolites in the plasma and tissues of the Npc1(-/-) mouse model and found several cholesterol oxidation products that were elevated in Npc1(-/-) mice, were detectable before the onset of symptoms, and were associated with disease progression. Nonenzymatically formed cholesterol oxidation products were similarly increased in the plasma of all human NPC1 subjects studied and delineated an oxysterol profile specific for NPC1 disease. This oxysterol profile also correlated with the age of disease onset and disease severity. We further show that the plasma oxysterol markers decreased in response to an established therapeutic intervention in the NPC1 feline model. These cholesterol oxidation products are robust blood-based biochemical markers for NPC1 disease that may prove transformative for diagnosis and treatment of this disorder, and as outcome measures to monitor response to therapy.
Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Forbes D
FD
Porter
David E
DE
Scherrer
Michael H
MH
Lanier
S Joshua
SJ
Langmade
Vasumathi
V
Molugu
Sarah E
SE
Gale
Dana
D
Olzeski
Rohini
R
Sidhu
Dennis J
DJ
Dietzen
Rao
R
Fu
Christopher A
CA
Wassif
Nicole M
NM
Yanjanin
Steven P
SP
Marso
John
J
House
Charles
C
Vite
Jean E
JE
Schaffer
Daniel S
DS
Ory
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000737:chemistry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015394:Molecular Structure; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood* / Q000503:physiopathology; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity
D015415:Biomarkers; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol