Blood Transcriptomic Meta-analysis Identifies Dysregulation of Hemoglobin and Iron Metabolism in Parkinson’ Disease

Santiago, José A.; Potashkin, Judith A.

doi:10.3389/fnagi.2017.00073

Cited by 28 publications

(26 citation statements)

References 53 publications

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“…Notably, a significant loss of negative co-expression between SNCA and interferon-gamma genes in the substantia nigra has been demonstrated in PD patients as compared to controls 42 . This loss may result from a downregulation of genes within M47 in the substantia nigra of PD patients, similarly as was observed in PD blood transcriptomics 39–41 . Therefore, these genes have the potential to serve as blood biomarkers for PD vulnerability.…”

Section: Discussionsupporting

confidence: 52%

“…One previous case-control study showed that anemia or low hemoglobin levels may precede the onset of PD 38 . Several studies using blood transcriptomic meta-analysis revealed genes associated with hemoglobin and iron metabolism were downregulated in PD patients compared to controls 39–41 . In our study, several hemoglobin genes ( HBD, HBB, HBA1 , HBA2 , and OASL ) were also present in module M47 of which HBD and HBB have been described to be highly interconnected with SNCA 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies using blood transcriptomic meta-analysis revealed genes associated with hemoglobin and iron metabolism were downregulated in PD patients compared to controls 39–41 . In our study, several hemoglobin genes ( HBD, HBB, HBA1 , HBA2 , and OASL ) were also present in module M47 of which HBD and HBB have been described to be highly interconnected with SNCA 41 . We also found an association between the interferon-gamma-mediated signaling pathway and M47 in which OASL also plays a role.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo

Mahfouz

Ingrassia

et al. 2019

Preprint

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25The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in 26Parkinson's disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures 27 across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. 28Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we 29 identified expression patterns related to PD progression, including genes found in PD genome-wide 30 associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these 31 patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain 32 Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-33 expression analysis across vulnerable regions identified two modules associated with dopamine 34 synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and 35 endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may 36 contribute to the selective regional vulnerability in PD brains. 37 38 3 Background 39 Parkinson's disease (PD) is characterized by a temporal caudal-rostral progression of Lewy body (LB) 40 pathology across a selected set of nuclei in the brain 1 . The distribution pattern of LB pathology is divided 41 into six Braak stages based on accumulation of the protein α-synucleinthe main component of LBs and 42 Lewy neuritesin the brainstem, limbic and neocortical regions 1 . Different hypotheses have been 43 brought forward to explain the evolving LB pathology across the brain, including: retrograde transport of 44 pathological α-synuclein via neuroanatomical networks, α-synuclein's prion-like behavior, and cell-or 45 region-autonomous factors 2,3 . Yet, the mechanisms underlying the selective vulnerability of brain regions 46 to LB pathology remains poorly understood, limiting the ability to diagnose and treat PD. 47 Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD 48and SNCA dosage has been linked to the severity of PD 4,5 . For other PD-associated variants, e.g. GBA 49and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been 50 associated with mitochondrial (dys)function and/or protein degradation pathways [6][7][8] . On the other hand, 51 transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the 52 substantia nigra, have identified several molecular mechanisms underlying PD pathology, including 53 synaptic vesicle endocytosis [9][10][11] . However, post-mortem human brain tissue of well-characterized PD 54 patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited 55 coverage of patients with different Braak LB stages, resulting in low concordance of findings across 56 different studies 12 . 57Spatial gene expression patterns in the human ...

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo

Mahfouz

Ingrassia

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Notably, a significant loss of negative co-expression between SNCA and interferon-gamma genes in the substantia nigra has been demonstrated in PD patients as compared to controls 41 . This loss may result from a downregulation of genes within M47 in the substantia nigra of PD patients, similarly as was observed in blood transcriptomics of PD [38][39][40] . This could be confirmed for ATXN3 in the substantia nigra of PD patients 42 .…”

Section: Discussionmentioning

confidence: 56%

“…One previous case-control study showed that anemia or low hemoglobin levels may precede the onset of PD 37 . Several studies using blood transcriptomic meta-analysis revealed genes associated with hemoglobin and iron metabolism were downregulated in PD patients compared to controls [38][39][40] . In our study, several hemoglobin genes (HBD, HBB, HBA1, HBA2, and OASL) were also present in module M47 of which HBD and HBB have been described to be highly interconnected with SNCA 40 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

et al. 2020

View full text Add to dashboard Cite

The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of nonneurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.

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Discovering Common Pathogenic Mechanisms of COVID-19 and Parkinson Disease: An Integrated Bioinformatics Analysis

et al. 2022

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Coronavirus disease 2019 (COVID-19) has emerged since December 2019 and was later characterized as a pandemic by WHO, imposing a major public health threat globally. Our study aimed to identify common signatures from different biological levels to enlighten the current unclear association between COVID-19 and Parkinson's disease (PD) as a number of possible links, and hypotheses were reported in the literature. We have analyzed transcriptome data from peripheral blood mononuclear cells (PBMCs) of both COVID-19 and PD patients, resulting in a total of 81 common differentially expressed genes (DEGs). The functional enrichment analysis of common DEGs are mostly involved in the complement system, type II interferon gamma (IFNG) signaling pathway, oxidative damage, microglia pathogen phagocytosis pathway, and GABAergic synapse. The protein-protein interaction network (PPIN) construction was carried out followed by hub detection, revealing 10 hub genes (MX1, IFI27, C1QC, C1QA, IFI6, NFIX, C1S, XAF1, IFI35, and ELANE). Some of the hub genes were associated with molecular mechanisms such as Lewy bodies-induced inflammation, microglia activation, and cytokine storm. We investigated regulatory elements of hub genes at transcription factor and miRNA levels. The major transcription factors regulating hub genes are SOX2, XAF1, RUNX1, MITF, and SPI1. We propose that these events may have important roles in the onset or progression of PD. To sum up, our analysis describes possible mechanisms linking COVID-19 and PD, elucidating some unknown clues in between. Keywords COVID-19• Parkinson disease • Transcriptome analysis • Regulatory networks • Signaling pathways • Bioinformatics Abbreviations BP Biological process CC Cellular component CNS Central nervous system COVID-19 Coronavirus disease 2019 CS Cytokine storm ETS E26 transformation-specific * Javad Zahiri

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Blood Transcriptomic Meta-analysis Identifies Dysregulation of Hemoglobin and Iron Metabolism in Parkinson’ Disease

Cited by 28 publications

References 53 publications

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Discovering Common Pathogenic Mechanisms of COVID-19 and Parkinson Disease: An Integrated Bioinformatics Analysis

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