Biosignatures for Parkinson’s Disease and Atypical Parkinsonian Disorders Patients

Potashkin, Judith A.; Santiago, José A.; Ravina, Bernard; Watts, Arthur; Leontovich, Alexey A.

doi:10.1371/journal.pone.0043595

Cited by 54 publications

(96 citation statements)

References 72 publications

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“…In particular, changes in mRNA from cellular whole blood can facilitate the identification of dysregulated processes and diagnostic biomarkers for PD (1,2). Several molecular signatures in blood have been identified.…”

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confidence: 99%

“…For example, 22 unique genes were found differentially expressed in blood of PD patients compared with healthy controls (1). Likewise, specific splice variants in blood were associated with PD in samples obtained from two independent clinical trials (2,3). In addition, altered expression of the vitamin D receptor (VDR) in blood and reduced plasma levels of 25-hydroxy vitamin D 3 have been associated with PD (1,4).…”

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confidence: 99%

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Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Networkbased metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were upand down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y followup period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.Parkinson's disease | HNF4A | PTBP1 | network analysis | blood biomarkers S ubstantial efforts have been devoted to the development of diagnostic strategies for Parkinson's disease (PD). In particular, changes in mRNA from cellular whole blood can facilitate the identification of dysregulated processes and diagnostic biomarkers for PD (1, 2). Several molecular signatures in blood have been identified. For example, 22 unique genes were found differentially expressed in blood of PD patients compared with healthy controls (1). Likewise, specific splice variants in blood were associated with PD in samples obtained from two independent clinical trials (2, 3). In addition, altered expression of the vitamin D receptor (VDR) in blood and reduced plasma levels of 25-hydroxy vitamin D 3 have been associated with PD (1, 4). Furthermore, plasma levels of the epidermal growth factor have been associated with cognitive decline in PD (5).Environmental stressors and genetic factors are most likely involved in the pathogenesis of PD. Among the genetic factors associated with PD, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal dominant PD (6) and a considerable risk factor in idiopathic forms of the disease (7,8). Given the complex interaction between environmental and genetic factors in sporadic PD, we integrated four independent microarray s...

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confidence: 99%

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confidence: 99%

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, mutations in APP linked to familial Alzheimer's disease increase the extracellular concentration of amyloid b protein (Ab) in vivo [31]. More recently, cerebrospinal fluid (CSF) concentrations of Ab peptides have been widely used to study Alzheimer's disease pathology in vivo and their utility to diagnose Parkinson's disease with dementia is under evaluation [32]. In addition to Alzheimer's disease, other neurological disorders including Down's syndrome, autism, and epilepsy are characterized by elevated expression of APP [33].…”

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confidence: 99%

Splice Variant Biomarkers for Parkinson's Disease

Potashkin¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEMay PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERRosalind Franklin U. Medicine & Science 3333 Green Bay Rd. North Chicago, IL 60064-3037 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTRecently we identified splice variants in whole blood than can distinguish early stage Parkinson's disease (PD) patients from healthy and neurodegenerative controls. The proposed studies will test the hypothesis that the biomarkers will be useful for identifying individuals at risk for PD and for identifying signaling pathways that are disrupted in PD. We are testing the expression of the biomarkers in RNA prepared from whole blood of hyposmic participants in the Parkinson's Associated Risk Study (PARS) (Technical Objective 1.0). In order to establish a model for testing the function of the biomarkers, we are determining whether their expression is altered in human olfactory neurosphere-derived (hONS) cells derived from idiopathic PD patients and healthy controls (Technical Objective 2.0). To determine the signaling pathways affected in PD and identify additional biomarkers, we are using network analysis (Technical Objective 3.0). During year 1, RNA and cDNA was prepared from PARS samples from Year 0 (baseline) and Year 2. Quantitative polymerase chain reactions were initiated for two of the biomarkers (APP, HNF4α). Expression of the biomarkers was tested in hONS. We also developed network approaches to reveal the common molecular pathways involved with PD and type 2 diabetes (T2DM). Using these networks, we identified APP, HNF4A and SOD2 mRNAs as blood biomarkers predictive of early stage PD. In addition, we determined that HNF4A mRNA may be a progression marker in blood for PD. SUBJECT TERMSParkinson's disease, biomarkers, neurodegeneration, network and pathway analysis 12-15Santiago 16-23Sei...

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“…Contrary to what the authors suggest, we are cognizant that several markers will be required to accurately identify earlystage PD patients. Our previous studies identified several markers, most of which were replicated in two independent clinical trials (3,4). It is our view that a combination of RNA and biochemical markers in blood and cerebrospinal fluid, for example, will be required for accurate diagnosis.…”

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confidence: 90%