Molecular markers of early Parkinson's disease based on gene expression in blood

Scherzer, Clemens R.; Eklund, Aron C.; Morse, Lee Jae; Liao, Zhixiang; Locascio, Joseph J.; Fefer, Daniel; Schwarzschild, Michael A.; Schlossmacher, Michael G.; Hauser, Michael A.; Vance, Jeffery M.; Sudarsky, Lewis; Standaert, David G.; Growdon, John H.; Jensen, Roderick V.; Gullans, Steven R.

doi:10.1073/pnas.0610204104

Cited by 448 publications

(395 citation statements)

References 48 publications

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“…Additionally, glucocorticoids have effects on peripheral blood cells and the hypothalamus-pituitary adrenal (HPA) axis, which is perturbed during depressive episodes of many patients (Gladkevich et al, 2004). Transcriptional profiling in whole blood has been used in the search for biomarkers for patients with neurological and other psychiatric disorders including patients with Parkinson's (Scherzer et al, 2007) and Huntington's disease (Borovecki et al, 2005), post-traumatic stress disorder Segman et al, 2005;Yehuda et al, 2009), schizophrenia (Kurian et al, 2011), bipolar disorder (Le-Niculescu et al, 2009;Padmos et al, 2008) and major depression (Segman et al, 2010;Spijker et al, 2010). Most of these studies have analyzed baseline gene expression profiles.…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients

Menke

Arloth

Pütz

et al. 2012

Neuropsychopharmacol

145

126

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Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies using baseline gene expression profiles have provided mixed results, our approach was to use an in vivo dexamethasone challenge test and to compare glucocorticoid receptor (GR)-mediated changes in gene expression between depressed patients and healthy controls. Whole genome gene expression data (baseline and following GR-stimulation with 1.5 mg dexamethasone p.o.) from two independent cohorts were analyzed to identify gene expression pattern that would predict case and control status using a training (N ¼ 18 cases/18 controls) and a test cohort (N ¼ 11/13). Dexamethasone led to reproducible regulation of 2670 genes in controls and 1151 transcripts in cases. Several genes, including FKBP5 and DUSP1, previously associated with the pathophysiology of major depression, were found to be reliable markers of GR-activation. Using random forest analyses for classification, GR-stimulated gene expression outperformed baseline gene expression as a classifier for case and control status with a correct classification of 79.1 vs 41.6% in the test cohort. GR-stimulated gene expression performed best in dexamethasone non-suppressor patients (88.7% correctly classified with 100% sensitivity), but also correctly classified 77.3% of the suppressor patients (76.7% sensitivity), when using a refined set of 19 genes. Our study suggests that in vivo stimulated gene expression in peripheral blood cells could be a promising molecular marker of altered GR-functioning, an important component of the underlying pathology, in patients suffering from depressive episodes.

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Section: Introductionmentioning

confidence: 99%

Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients

Menke

Arloth

Pütz

et al. 2012

Neuropsychopharmacol

145

126

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“…A Volcano plot was used to identify differentially expressed genes by comparing the SNCA duplication carrier in triplicate to the controls, using a ≥1.2-fold change and p<0.05 as the significance threshold (Welch's t-test). Furthermore, we compared our results with the significantly deregulated genes (p<0.05 t-test) from (i) an Affymetrix transcriptomic analysis of PBMCs between 50 PD patients and 22 controls from the GEO dataset GDS2519 (www.ncbi.nlm.nih.gov/sites/gds) (Scherzer et al, 2007) and (ii) an Affymetrix transcriptomic analysis of substantia nigra between 16 PD patients and 9 controls from the GEO dataset GDS2821 (Lesnick et al, 2007).…”

Section: Microarray Proceduresmentioning

confidence: 99%

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes

et al. 2011

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Genomic multiplication of the alpha-synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non-allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN ® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype-phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication.

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“…Several investigators have demonstrated differential expression of genes in peripheral white blood cells in disorders of the central nervous system. [10][11][12][13] The fi ndings from that research may suggest that altered miRNA expression profi les target genes closely involved in neurological functions and disorders and, in turn, may lead to the pathophysiological conditions associated with autism. Altered expression of cellular and circulating miRNAs have been observed in autistic individuals compared to healthy controls.…”

mentioning

confidence: 99%

Profiling of Circulating Serum MicroRNAs in Children with Autism Spectrum Disorder using Stem-loop qRT-PCR Assay

Kichukova¹,

Popov²,

Ivanov³

et al. 2017

Folia Medica

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Citation: Kichukova TM, Popov NT, Ivanov IS, Vachev TI. Profi ling of circulating serum microRNAs in children with autism spectrum disorder using stem-loop qRT-PCR assay.Folia Medica 2017;59(1): 43-52. doi: 10.1515/folmed-2017-0009 Background: Development of biomarkers for autism spectrum disorder (ASD) has still remained a challenge to date. Recently, alterations of the expression of microRNAs (miRNAs) in peripheral blood, serum and post-mortem brain tissue have been linked to ASD. miRNAs are known to be secreted by various cell types and can mediate transmission of information into recipient cells and to modulate their physiological functions. On this basis it is assumed that circulating miRNAs could be useful biomarkers for the diagnosis or prognosis of pathological conditions. Aim: The aim of this study was to test whether circulating miRNAs display diff erential expression profi le in serum of ASD patients. Patients and methods:The relative expression levels of 42 miRNAs were analyzed by stem-loop qRT-PCR assay in the serum of ASD patients compared to healthy controls. Results: The results indicated that 11 miRNAs in ASD patients were substantially higher expressed than these in control subjects, and 29 miRNAs were lower expressed, respectively. In addition, target gene analysis displayed that the altered serum miRNAs targeted some important genes like alpha 1C subunit of voltagedependent calcium channel, L type, (CACNA1C), beta 1 subunit of voltage-dependent calcium channel (CACNB1) and other genes involved in epigenetic processes like dicer 1, coding ribonuclease type III (DICER). Conclusion: Our results suggested that diff erentially expressed miRNAs in serum might be involved in ASD molecular pathways, and serum miR- 424-5p, miR-197-5p, miR-328-3p, miR-500a-5p, miR-619-5p, miR-3135a, miR-664a-3p, and miR365a-3p might be able to serve as potential biomarkers for ASD because they displayed signifi cant alterations in the expression profi le in children diagnosed with ASD.

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Molecular markers of early Parkinson's disease based on gene expression in blood

Cited by 448 publications

References 48 publications

Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients

Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes

Profiling of Circulating Serum MicroRNAs in Children with Autism Spectrum Disorder using Stem-loop qRT-PCR Assay

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