scholarly journals Transcriptomic profiles in Parkinson’s disease

2020 ◽  
pp. 153537022096732
Author(s):  
Lille Kurvits ◽  
Freddy Lättekivi ◽  
Ene Reimann ◽  
Liis Kadastik-Eerme ◽  
Kristjan M Kasterpalu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Brain Tissue ◽  
Differentially Expressed Genes ◽  
Meta Analysis ◽  
Rank Aggregation ◽  
Differentially Expressed ◽  
Peripheral Tissues

Transcriptomics in Parkinson’s disease offers insights into the pathogenesis of Parkinson’s disease but obtaining brain tissue has limitations. In order to bypass this issue, we profile and compare differentially expressed genes and enriched pathways (KEGG) in two peripheral tissues (blood and skin) of 12 Parkinson’s disease patients and 12 healthy controls using RNA-sequencing technique and validation with RT-qPCR. Furthermore, we compare our results to previous Parkinson’s disease post mortem brain tissue and blood results using the robust rank aggregation method. The results show no overlapping differentially expressed genes or enriched pathways in blood vs. skin in our sample sets (25 vs. 1068 differentially expressed genes with an FDR ≤ 0.05; 1 vs. 9 pathways in blood and skin, respectively). A meta-analysis from previous transcriptomic sample sets using either microarrays or RNA-Seq yields a robust rank aggregation list of cortical gene expression changes with 43 differentially expressed genes; a list of substantia nigra changes with 2 differentially expressed genes and a list of blood changes with 1 differentially expressed gene being statistically significant at FDR ≤ 0.05. In cortex 1, KEGG pathway was enriched, four in substantia nigra and two in blood. None of the differentially expressed genes or pathways overlap between these tissues. When comparing our previously published skin transcription analysis, two differentially expressed genes between the cortex robust rank aggregation and skin overlap. In this study, for the first time a meta-analysis is applied on transcriptomic sample sets in Parkinson’s disease. Simultaneously, it explores the notion that Parkinson’s disease is not just a neuronal tissue disease by exploring peripheral tissues. The comparison of different Parkinson’s disease tissues yields surprisingly few significant differentially expressed genes and pathways, suggesting that divergent gene expression profiles in distinct cell lineages, metabolic and possibly iatrogenic effects create too much transcriptomic noise for detecting significant signal. On the other hand, there are signs that point towards Parkinson’s disease-specific changes in non-neuronal peripheral tissues in Parkinson’s disease, indicating that Parkinson’s disease might be a multisystem disorder.

scholarly journals Meta-Analysis of Differentially Expressed Genes in the Substantia Nigra in Parkinson’s Disease Supports Phenotype-Specific Transcriptome Changes

2020 ◽  
Vol 14 ◽  
Author(s):  
Duong My Phung ◽  
Jinwoo Lee ◽  
SangKyoon Hong ◽  
Young Eun Kim ◽  
Jeehee Yoon ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Differentially Expressed Genes ◽  
Neurodegenerative Disorder ◽  
Meta Analysis ◽  
Differentially Expressed ◽  
Cell Type ◽  
Progressive Ataxia ◽  
Upregulated Genes

BackgroundStudies regarding differentially expressed genes (DEGs) in Parkinson’s disease (PD) have focused on common upstream regulators or dysregulated pathways or ontologies; however, the relationships between DEGs and disease-related or cell type-enriched genes have not been systematically studied. Meta-analysis of DEGs (meta-DEGs) are expected to overcome the limitations, such as replication failure and small sample size of previous studies.PurposeMeta-DEGs were performed to investigate dysregulated genes enriched with neurodegenerative disorder causative or risk genes in a phenotype-specific manner.MethodsSix microarray datasets from PD patients and controls, for which substantia nigra sample transcriptome data were available, were downloaded from the NINDS data repository. Meta-DEGs were performed using two methods, combining p-values and combing effect size, and common DEGs were used for secondary analyses. Gene sets of cell type-enriched or disease-related genes for PD, Alzheimer’s disease (AD), and hereditary progressive ataxia were constructed by curation of public databases and/or published literatures.ResultsOur meta-analyses revealed 449 downregulated and 137 upregulated genes. Overrepresentation analyses with cell type-enriched genes were significant in neuron-enriched genes but not in astrocyte- or microglia-enriched genes. Meta-DEGs were significantly enriched in causative genes for hereditary disorders accompanying parkinsonism but not in genes associated with AD or hereditary progressive ataxia. Enrichment of PD-related genes was highly significant in downregulated DEGs but insignificant in upregulated genes.ConclusionDownregulated meta-DEGs were associated with PD-related genes, but not with other neurodegenerative disorder genes. These results highlight disease phenotype-specific changes in dysregulated genes in PD.

scholarly journals Correcting differential gene expression analysis for cyto-architectural alterations in substantia nigra of Parkinson's disease patients reveals known and potential novel disease-associated genes and pathways

2021 ◽  
Author(s):  
Federico Ferraro ◽  
Christina Fevga ◽  
Vincenzo Bonifati ◽  
Wim Mandemakers ◽  
Ahmed Mahfouz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Substantia Nigra Pars Compacta ◽  
Ammonium Transport ◽  
Protein Interaction Data

Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson's disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might be caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artifacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes including bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein-interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, and PRKN known to be related to PD; others with compelling evidence for their role in neurodegeneration, such as GSK3β, WWOX, and VPC; as well as novel potential players in the PD pathogenesis, including NTRK1, TRIM25, ELAVL1. Together, these data showed the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology providing potential new targets for drug development.

scholarly journals Correcting Differential Gene Expression Analysis for Cyto—Architectural Alterations in Substantia Nigra of Parkinson’s Disease Patients Reveals Known and Potential Novel Disease—Associated Genes and Pathways

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 198
Author(s):  
Federico Ferraro ◽  
Christina Fevga ◽  
Vincenzo Bonifati ◽  
Wim Mandemakers ◽  
Ahmed Mahfouz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Substantia Nigra Pars Compacta ◽  
Ammonium Transport ◽  
Protein Interaction Data

Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson’s disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might have been caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artefacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes such as bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, PRKN, and FBXO7, known to be related to PD, others with compelling evidence for their role in neurodegeneration, such as GSK3β, WWOX, and VPC, and novel potential players in the PD pathogenesis. Together, these data show the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology, providing potential new targets for drug development.

scholarly journals Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson’s Disease Patients

2021 ◽  
Vol 14 ◽  
Author(s):  
Katarína Tiklová ◽  
Linda Gillberg ◽  
Nikolaos Volakakis ◽  
Hilda Lundén-Miguel ◽  
Lina Dahl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Lewy Body Disease ◽  
Dopamine Neurons ◽  
Differentially Expressed ◽  
Incidental Lewy Body Disease ◽  
Advanced Stages ◽  
Midbrain Dopamine

Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.

scholarly journals HIV-1 Infection Transcriptomics: Meta-Analysis of CD4+ T Cells Gene Expression Profiles

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 244 ◽  
Author(s):  
Antonio Victor Campos Coelho ◽  
Rossella Gratton ◽  
João Paulo Britto de Melo ◽  
José Leandro Andrade-Santos ◽  
Rafael Lima Guimarães ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Differentially Expressed Genes ◽  
Cd4 T Cells ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Infected Cells ◽  
Hiv 1

HIV-1 infection elicits a complex dynamic of the expression various host genes. High throughput sequencing added an expressive amount of information regarding HIV-1 infections and pathogenesis. RNA sequencing (RNA-Seq) is currently the tool of choice to investigate gene expression in a several range of experimental setting. This study aims at performing a meta-analysis of RNA-Seq expression profiles in samples of HIV-1 infected CD4+ T cells compared to uninfected cells to assess consistently differentially expressed genes in the context of HIV-1 infection. We selected two studies (22 samples: 15 experimentally infected and 7 mock-infected). We found 208 differentially expressed genes in infected cells when compared to uninfected/mock-infected cells. This result had moderate overlap when compared to previous studies of HIV-1 infection transcriptomics, but we identified 64 genes already known to interact with HIV-1 according to the HIV-1 Human Interaction Database. A gene ontology (GO) analysis revealed enrichment of several pathways involved in immune response, cell adhesion, cell migration, inflammation, apoptosis, Wnt, Notch and ERK/MAPK signaling.

scholarly journals A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

2020 ◽  
Author(s):  
Sejal Patel ◽  
Derek Howard ◽  
Leon French
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Human Brain ◽  
Disease Risk ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Postmortem Human Brain ◽  
Increased Risk

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

DNA-methylation analysis of differentially expressed genes in fibroblast cell-lines, derived from monozygotic twins discordant for Parkinson’s disease

2020 ◽  
pp. 73-74
Author(s):  
И.Н. Рыболовлев ◽  
И.Н. Власов ◽  
А.Х. Алиева ◽  
П.А. Сломинский ◽  
М.И. Шадрина
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Regulation Of Gene Expression ◽  
Monozygotic Twins ◽  
Fibroblast Cell ◽  
Differentially Expressed ◽  
Pathogenesis Related

Болезнь Паркинсона (БП) является многофакторным гетерогенным нейродегенеративным заболеванием. Поскольку этиопатогенез БП недостаточно изучен, кроме поиска и анализа изменений на уровне ДНК, необходимо распространить фокус исследований на другие уровни: транскриптом и метилом. Изменения на уровне эпигенома можно исследовать у лиц с идентичной генетической конституцией, такой «моделью» являются дискордантные по этому заболеванию монозиготные близнецы. В исследовании приняло участие 3 пары фенотипически и генотипически монозиготных близнецов русского происхождения; В исследовании приняло участие 3 пары фенотипически и генотипически монозиготных близнецов русского происхождения. БП была уточнена у одного из каждой пары близнецов; длительность течения болезни у близнеца с БП составило по меньшей мере 7 лет.; длительность течения болезни у близнеца с БП составила по меньшей мере 7 лет. Были проанализированы метиломы крови и отобраны точки варьирующегося метилирования. Нами было найдено 8 дифференциально экспрессирующихся генов, которые могут быть дифференциально метилированы. Были выявлены различия между здоровым близнецом и близнецом с БП по уровню метилирования ДНК для ряда этих генов в клеточных линиях фибробластов. Полученные нами данные могут указывать на участие процесса ДНК-метилирования в регуляции транскрипции кандидатных генов-участников патогенеза БП. In recent years it has been convincingly demonstrated that genetic factors play an important role in progression of Parkinson’s disease (PD). Since the etiology of PD has not been elucidated completely yet, it is crucial to shift focus of the research to the broader areas - to dive into investigations of methylome and transcriptome. Epigenetic regulation of gene expression may take part in pathogenesis of PD. Changes in epigenome can be conveniently investigated in case of individuals with almost identical genetic makeup, and monozygotic twins discordant for PD may be such “model”. 3 pairs phenotypically and genotypically monozygous twins of Russian ancestry were enrolled in the study. PD was diagnosed in one of each pair. The disease duration was at least 7 years. Data on blood methylomes was analyzed. Points of variable methylation in blood methylomes were selected. With this approach, 8 differentially expressed genes were found that also may be differentially methylated. Changes in methylation level for some of this genes were found in monozygotic twins discordant for PD fibroblasts cell-lines between healthy and afflicted siblings. Acquired data might suggest participation of DNA-methylation in transcription regulation of PD pathogenesis-related candidate genes.

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