DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease

Lin, Xiangmin; Cook, Travis J.; Zabetian, Cyrus P.; Leverenz, James B.; Peskind, Elaine R.; Hu, Shu‐Ching; Cain, Kevin C.; Pan, Catherine; Edgar, J. Scott; Racette, Brad A.; Checkoway, Harvey; Montine, Thomas J.; Shi, Min; Zhang, Jing

doi:10.1038/srep00954

Cited by 95 publications

(63 citation statements)

References 42 publications

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“…The protein concentration of individual samples was determined using the Pierce bicinchoninic acid (BCA) Protein Assay Kit (Thermo Scientific, Rockford, IL). The proteins were then reduced and alkylated using dithiothreitol and iodoacetamide, respectively, followed by trypsin digestion as described previously (24,27).…”

Section: Methodsmentioning

confidence: 99%

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Shi

Movius

Dator

et al. 2015

Molecular & Cellular Proteomics

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a Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent technical limitations associated with imaging or antibody-based protein assays.To circumvent the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter study consisting of training and validation sets, a total of 178 subjects were randomly selected from a retrospective cohort, matching age and sex between PD patients, healthy controls, and neurological controls with Alzheimer disease (AD). From ϳ14,000 unique peptides displaying differences between PD and healthy control in proteomic investigations, 126 peptides were selected based on relevance and observability in CSF using bioinformatic analysis and MS screening, and then quantified by highly accurate and sensitive selected reaction monitoring (SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1, LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of 0.873 (sensitivity ‫؍‬ 76.7%, specificity ‫؍‬ 80.0%) for PD versus healthy controls in the training set. The performance was essentially confirmed in the validation set (AUC ‫؍‬ 0.853, sensitivity ‫؍‬ 82.5%, specificity ‫؍‬ 82.5%). Additionally, this panel could also differentiate the PD and AD groups (AUC ‫؍‬ 0.990, sensitivity ‫؍‬ 95.0%, specificity ‫؍‬ 97.4%). Furthermore, a combination of two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the training (r ‫؍‬ 0.381, p ‫؍‬ 0.038)j and the validation (r ‫؍‬ 0.339, p ‫؍‬ 0.032) sets. The novel panel of CSF peptides, if validated in independent co-

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Section: Methodsmentioning

confidence: 99%

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Shi

Movius

Dator

et al. 2015

Molecular & Cellular Proteomics

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“…In a study of seven DJ-1 isoforms detected in blood, those with post-translational 4-hydroxy-2-nonenal modifications were altered in late PD. 61 In an independent study, DJ-1 oxidized on cysteine-106 specifically was found to be elevated in red blood cells in PD. 62 Initial results are therefore somewhat encouraging, with the caveat that careful consideration of …”

Section: Pd Genetics and Biomarker Developmentmentioning

confidence: 99%

Blood and cerebrospinal fluid markers in Parkinson's disease: current biomarker findings

Henchcliffe

2014

CBF

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Abstract:Parkinson's disease (PD) is a common, progressive, and disabling neurodegenerative movement disorder. Signs and symptoms begin insidiously and overlap with other neurodegenerative conditions, making diagnosis challenging in early disease. Moreover, there are as yet no established biomarkers that will objectively measure disease progression, and this hampers efforts to obtain neuroprotective therapies. At present, diagnosis, measurement of progression, and response to therapeutic intervention rely almost exclusively upon clinical observation. There remains, therefore, a critical need for validated biomarkers. Recent advances in understanding the underlying pathophysiology of PD have aided in identifying strong candidate markers to assist in diagnosis and evaluate progression. Pathways that are disrupted in PD include protein misfolding, mitochondrial dysfunction and increased oxidative stress, dysregulated inflammatory processes, and altered gene expression. For example, α-synuclein is a key contributor to PD pathology, in which misfolded and damaged α-synuclein accumulates in neurons; this is now a leading candidate as a PD biomarker in cerebrospinal fluid. There is also recent evidence that markers of Alzheimer's disease may be "repurposed" to provide information on PD diagnosis, prognosis, and nonmotor symptoms, including cognitive dysfunction. At the same time, increasingly sophisticated bioinformatics technology allows an unbiased approach to biomarker identification, for example, using proteomic, transcriptomic, and metabolomic analysis. Such generally accessible blood or cerebrospinal fluid tests, if successful, will likely lead to significant improvements in PD diagnosis, management, and research.

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“…Park7 expression is reduced in pancreatic islets of type 2 diabetic patients, where it may be required for mitochondrial function and glucosestimulated insulin secretion (42). Cerebrospinal, but not plasma, Park7 levels have been proposed as a biomarker of Parkinson disease (43,44), whereas 4-hydroxy-2-nonenal-modified Park7 could be a plasma biomarker of late-stage Parkinson (45).…”

Section: Discussionmentioning

confidence: 99%

Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic β Cell Dysfunction

Kuo

Kim-Muller

McGraw

et al. 2016

Journal of Biological Chemistry

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Insulin resistance and ␤ cell dysfunction contribute to the pathogenesis of type 2 diabetes. Unlike insulin resistance, ␤ cell dysfunction remains difficult to predict and monitor, because of the inaccessibility of the endocrine pancreas, the integrated relationship with insulin sensitivity, and the paracrine effects of incretins. The goal of our study was to survey the plasma response to a metabolic challenge in order to identify factors predictive of ␤ cell dysfunction. To this end, we combined (i) the power of unbiased iTRAQ (isobaric tag for relative and absolute quantification) mass spectrometry with (ii) direct sampling of the portal vein following an intravenous glucose/arginine challenge (IVGATT) in (iii) mice with a genetic ␤ cell defect. By so doing, we excluded the effects of peripheral insulin sensitivity as well as those of incretins on ␤ cells, and focused on the first phase of insulin secretion to capture the early pathophysiology of ␤ cell dysfunction. We compared plasma protein profiles with ex vivo islet secretome and transcriptome analyses. We detected changes to 418 plasma proteins in vivo, and detected changes to 262 proteins ex vivo. The impairment of insulin secretion was associated with greater overall changes in the plasma response to IVGATT, possibly reflecting metabolic instability. Reduced levels of proteins regulating redox state and neuronal stress markers, as well as increased levels of coagulation factors, antedated the loss of insulin secretion in diabetic mice. These results suggest that a reduced complement of antioxidants in response to a mixed secretagogue challenge is an early correlate of future ␤ cell failure.The incidence of diabetes has increased considerably (1). Type 2 diabetes is characterized by insulin resistance and impaired ␤ cell function (2). Both abnormalities contribute to the onset and progression of the disease. However, progression from pre-diabetes to diabetes is characterized by a steep decrease of insulin secretory function, whereas insulin resistance remains relatively constant (3, 4). It appears that even modest elevations of plasma glucose levels are toxic to ␤ cells (5). In addition, outcome studies have consistently demonstrated that diabetic patients treated with sulfonylurea-type secretagogues experience faster therapeutic failure rates that require the addition of a second medication, when compared with those treated with insulin sensitizers (6). These facts point to two conclusions: (i) that there is an intrinsic impairment of ␤ cell function in diabetes; and (ii) that promoting insulin secretion does not redress the problem.To develop better therapies and increase the sensitivity of probing ␤ cell function, it would be desirable to have markers predictive of ␤ cell failure. Sensitive tests of insulin secretion are rarely applicable as routine diagnostics, and have limited predictive value of response to treatment. Given the renewed focus on durability as a key criterion to develop more efficacious diabetes treatments (7), it is essential to eva...

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DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease

Cited by 95 publications

References 42 publications

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Blood and cerebrospinal fluid markers in Parkinson's disease: current biomarker findings

Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic β Cell Dysfunction

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DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease

Cited by 95 publications

References 42 publications

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Blood and cerebrospinal fluid markers in Parkinson&#39;s disease: current biomarker findings

Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic β Cell Dysfunction

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Blood and cerebrospinal fluid markers in Parkinson's disease: current biomarker findings