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The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

Original publication

DOI

10.1021/pr5006058

Type

Journal article

Journal

J Proteome Res

Publication Date

07/11/2014

Volume

13

Pages

4518 - 4525

Keywords

Alzheimer’s disease, Creutzfeldt−Jakob disease, MRM, Parkinson’s disease, Ubiquitin, amyotrophic lateral sclerosis, biomarker, cerebrospinal fluid, frontotemporal lobar degeneration, mass spectrometry, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Aphasia, Primary Progressive, Area Under Curve, Biomarkers, Chromatography, Liquid, Creutzfeldt-Jakob Syndrome, Frontotemporal Lobar Degeneration, Humans, Parkinson Disease, ROC Curve, Sensitivity and Specificity, Supranuclear Palsy, Progressive, Tandem Mass Spectrometry, Ubiquitin