Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease)
Autor: | Jonathan P. Dyke, Barry E. Kosofsky, Dolan Sondhi, Douglas Ballon, Stephen M. Kaminsky, Miriam Sindelar, Ronald G. Crystal, Steven S. Gross, Ruba S. Deeb |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male Metabolite lcsh:Medicine Disease Acetates Aminopeptidases Severity of Illness Index chemistry.chemical_compound Cerebrospinal fluid Child lcsh:Science Neurons Multidisciplinary Tripeptidyl-Peptidase 1 Neurodegeneration Brain Middle Aged 3. Good health Mitochondria Child Preschool Metabolome Female Adult Batten disease Adolescent Article Lipofuscin 03 medical and health sciences Young Adult Metabolomics Neuronal Ceroid-Lipofuscinoses Severity of illness medicine Animals Humans Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Aged business.industry lcsh:R medicine.disease Disease Models Animal 030104 developmental biology chemistry Immunology lcsh:Q Serine Proteases business Biomarkers |
Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare lysosomal storage disorder caused by a monogenetic deficiency of tripeptidyl peptidase-1 (TPP1). Despite knowledge that lipofuscin is the hallmark disease product, the relevant TPP1 substrate and its role in neuronal physiology/pathology is unknown. We hypothesized that untargeted metabolite profiling of cerebrospinal fluid (CSF) could be used as an effective tool to identify disease-associated metabolic disruptions in CLN2 disease, offering the potential to identify biomarkers that inform on disease severity and progression. Accordingly, a mass spectrometry-based untargeted metabolite profiling approach was employed to differentiate CSF from normal vs. CLN2 deficient individuals. Of 1,433 metabolite features surveyed, 29 linearly correlated with currently employed disease severity scores. With tandem mass spectrometry 8 distinct metabolite identities were structurally confirmed based on retention time and fragmentation pattern matches, vs. standards. These putative CLN2 biomarkers include 7 acetylated species – all attenuated in CLN2 compared to controls. Because acetate is the major bioenergetic fuel for support of mitochondrial respiration, deficient acetylated species in CSF suggests a brain energy defect that may drive neurodegeneration. Targeted analysis of these metabolites in CSF of CLN2 patients offers a powerful new approach for monitoring CLN2 disease progression and response to therapy. |
Databáze: | OpenAIRE |
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