Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

Abstract

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.

• Authors: Patrick Oeckl, Petra Steinacker, Christine A F von Arnim, Sarah Straub, Magdalena Nagl, Emily Feneberg, Jochen H Weishaupt, Albert C Ludolph, Markus Otto
• Journal: Journal of proteome research (J Proteome Res) Vol. 13 Issue 11 Pg. 4518-25 (Nov 07 2014) ISSN: 1535-3907 [Electronic] United States
• PMID: 25091646 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Ubiquitin

Topics

• Alzheimer Disease (cerebrospinal fluid)
• Amyotrophic Lateral Sclerosis (cerebrospinal fluid)
• Aphasia, Primary Progressive (cerebrospinal fluid)
• Area Under Curve
• Biomarkers (cerebrospinal fluid)
• Chromatography, Liquid
• Creutzfeldt-Jakob Syndrome (cerebrospinal fluid)
• Frontotemporal Lobar Degeneration (cerebrospinal fluid)
• Humans
• Parkinson Disease (cerebrospinal fluid)
• ROC Curve
• Sensitivity and Specificity
• Supranuclear Palsy, Progressive (cerebrospinal fluid)
• Tandem Mass Spectrometry
• Ubiquitin (cerebrospinal fluid)