Dataset Information

Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders.

ABSTRACT:

Purpose

Dysfunctional proteostasis, with decreased protein degradation and an accumulation of ubiquitin into aggregated protein inclusions, is a feature of neurodegenerative diseases. Identifying new potential biomarkers in cerebrospinal fluid (CSF) reflecting this process could contribute important information on pathophysiology.

Experimental design

A developed method combining SPE and PRM-MS is employed to monitor the concentration of ubiquitin in CSF from subjects with Alzheimer's disease (AD), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). Four independent cross-sectional studies are conducted, studies 1-4, including controls (n = 86) and participants with AD (n = 60), PD (n = 15), and PSP (n = 11).

Results

The method shows a repeatability and intermediate precision not exceeding 6.1 and 7.9%, respectively. The determined LOD is 0.1 nm and the LOQ range between 0.625 and 80 nm. The CSF ubiquitin concentration is 1.2-1.5-fold higher in AD patients compared with controls in the three independent AD-control studies (Study 1, p < 0.001; Study 2, p < 0.001; and Study 3, p = 0.003). In the fourth study, there is no difference in PD or PSP, compared to controls.

Conclusion and clinical relevance

CSF ubiquitin may reflect dysfunctional proteostasis in AD. The described method can be used for further exploration of ubiquitin as a potential biomarker in neurodegenerative diseases.

SUBMITTER: Sjodin S

PROVIDER: S-EPMC5765402 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders.

Sjödin Simon S Hansson Oskar O Öhrfelt Annika A Brinkmalm Gunnar G Zetterberg Henrik H Brinkmalm Ann A Blennow Kaj K

Proteomics. Clinical applications 20171102 11-12

<h4>Purpose</h4>Dysfunctional proteostasis, with decreased protein degradation and an accumulation of ubiquitin into aggregated protein inclusions, is a feature of neurodegenerative diseases. Identifying new potential biomarkers in cerebrospinal fluid (CSF) reflecting this process could contribute important information on pathophysiology.<h4>Experimental design</h4>A developed method combining SPE and PRM-MS is employed to monitor the concentration of ubiquitin in CSF from subjects with Alzheime ...[more]

PMID: 28972305

Similar Datasets

Project description:IntroductionAlzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline. Protein biomarkers of AD brain pathology, including β-amyloid and Tau, are reflected in cerebrospinal fluid (CSF), yet the identification of additional biomarkers linked to other brain pathophysiologies remains elusive. We recently reported a multiplex tandem-mass tag (TMT) CSF proteomic analysis of nearly 3000 proteins, following depletion of highly abundant proteins and off-line fractionation, across control and AD cases. Of these, over 500 proteins were significantly increased or decreased in AD, including markers reflecting diverse biological functions in brain. Here, we use a targeted mass spectrometry (MS) approach, termed parallel reaction monitoring (PRM), to quantify select CSF biomarkers without pre-depletion or fractionation to assess the reproducibility of our findings and the specificity of changes for AD versus other causes of cognitive impairment.MethodWe nominated 41 proteins (94 peptides) from the TMT CSF discovery dataset, representing a variety of brain cell-types and biological functions, for label-free PRM analysis in a replication cohort of 88 individuals that included 20 normal controls, 37 clinically diagnosed AD cases and 31 cases with non-AD cognitive impairment. To control for technical variables, isotopically labeled synthetic heavy peptide standards were added into each of the 88 CSF tryptic digests. Furthermore, a peptide pool, representing an equivalent amount of peptide from all samples, was analyzed (n = 10) across each batch. Together, this approach enabled us to assess both the intra- and inter-sample differences in peptide signal response and retention time.ResultsDespite differences in sample preparation, quantitative MS approaches and patient samples, 25 proteins, including Tau, had a consistent and significant change in AD in both the discovery and replication cohorts. Validated CSF markers with low coefficient of variation included the protein products for neuronal/synaptic (GDA, GAP43, SYN1, BASP1, YWHAB, YWHAZ, UCHL1, STMN1 and MAP1B), glial/inflammation (SMOC1, ITGAM, CHI3L1, SPP1, and CHIT1) and metabolic (PKM, ALDOA and FABP3) related genes. Logistical regression analyses revealed several proteins with high sensitivity and specificity for classifying AD cases from controls and other non-AD dementias. SMOC1, YWHAZ, ALDOA and MAP1B emerged as biomarker candidates that could best discriminate between individuals with AD and non-AD cognitive impairment as well as Tau/β-amyloid ratio. Notably, SMOC1 levels in postmortem brain are highly correlated with AD pathology even in the preclinical stage of disease, indicating that CSF SMOC1 levels reflect underlying brain pathology specific for AD.ConclusionCollectively these findings highlight the utility of targeted MS approaches to quantify biomarkers associated with AD that could be used for monitoring disease progression, stratifying patients for clinical trials and measuring therapeutic response.

Dataset Information

Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders.

Purpose

Experimental design

Results

Conclusion and clinical relevance

Publications

Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets