Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression

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.

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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

10.1101/2021.05.25.445590 ◽

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.

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Reference SVA insertion polymorphisms are associated with Parkinson’s Disease progression and differential gene expression

npj Parkinson s Disease ◽

10.1038/s41531-021-00189-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Abigail L. Pfaff ◽

Vivien J. Bubb ◽

John P. Quinn ◽

Sulev Koks

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Differential Gene Expression ◽

Association Studies ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Regulatory Domains ◽

Differential Gene

AbstractThe development of Parkinson’s disease (PD) involves a complex interaction of genetic and environmental factors. Genome-wide association studies using extensive single nucleotide polymorphism datasets have identified many loci involved in disease. However much of the heritability of Parkinson’s disease is still to be identified and the functional elements associated with the risk to be determined and understood. To investigate the component of PD that may involve complex genetic variants we characterised the hominid specific retrotransposon SINE-VNTR-Alus (SVAs) in the Parkinson’s Progression Markers Initiative cohort utilising whole genome sequencing. We identified 81 reference SVAs polymorphic for their presence/absence, seven of which were associated with the progression of the disease and with differential gene expression in whole blood RNA sequencing data. This study highlights the importance of addressing SVA variants and potentially other types of retrotransposons in PD genetics, furthermore, these SVA elements should be considered as regulatory domains that could play a role in disease progression.

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Differential transcript usage in the Parkinson’s disease brain

PLoS Genetics ◽

10.1371/journal.pgen.1009182 ◽

2020 ◽

Vol 16 (11) ◽

pp. e1009182

Author(s):

Fiona Dick ◽

Gonzalo S. Nido ◽

Guido Werner Alves ◽

Ole-Bjørn Tysnes ◽

Gry Hilde Nilsen ◽

...

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Differential Gene Expression ◽

Reactive Oxygen Species Generation ◽

Protein Coding ◽

Independent Case ◽

Functional Consequences ◽

Differential Gene ◽

Disease Associated Genes

Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcript-count based approaches, implemented in the DRIMSeq and DEXSeq tools. Multiple PD-associated DTU events were detected in each cohort, of which 23 DTU events in 19 genes replicated across both patient cohorts. For several of these, including THEM5, SLC16A1 and BCHE, DTU was predicted to have substantial functional consequences, such as altered subcellular localization or switching to non-protein coding isoforms. Furthermore, genes with PD-associated DTU were enriched in functional pathways previously linked to PD, including reactive oxygen species generation and protein homeostasis. Importantly, the vast majority of genes exhibiting DTU were not differentially expressed at the gene-level and were therefore not identified by conventional differential gene expression analysis. Our findings provide the first insight into the DTU landscape of PD and identify novel disease-associated genes. Moreover, we show that DTU may have important functional consequences in the PD brain, since it is predicted to alter the functional composition of the proteome. Based on these results, we propose that DTU analysis is an essential complement to differential gene expression studies in order to provide a more accurate and complete picture of disease-associated transcriptomic alterations.

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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 ◽

10.3390/cells11020198 ◽

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.

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Reference SVA insertion polymorphisms are associated with dopaminergic degeneration in Parkinson’s Disease and differential gene expression in the PPMI cohort

10.21203/rs.3.rs-41600/v1 ◽

2020 ◽

Author(s):

Abigail L Pfaff ◽

Vivien J. Bubb ◽

John P. Quinn ◽

Sulev Koks

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Differential Gene Expression ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

Genome Wide ◽

Differential Gene

Abstract Background: The development of Parkinson’s disease (PD) involves a complex interaction of genetic and environmental factors. The majority of studies investigating the genetic component of complex diseases, including PD, have focused on single nucleotide polymorphisms as this enables genome wide analysis of a large number of samples. Genome wide association studies have been crucial in identifying PD risk variants, however a large proportion of the heritability of PD remains to be identified. To investigate the component of PD that may involve complex genetic variants we characterised SINE-VNTR-Alus (SVAs), a retrotransposon known to affect gene expression, in the Parkinson’s Progression Markers Initiative (PPMI) cohort.Results: Utilising whole genome sequencing from the PPMI cohort that consisted of 179 healthy controls, 371 individuals with PD and 58 individuals classified as SWEDD (scans without evidence of dopaminergic deficit) we genotyped SVAs in the reference genome for their presence or absence identifying 81 such SVAs. Seven of these SVAs were associated with progression of the disease, including four whose specific genotypes were linked to an increase in the gradient of dopaminergic loss when comparing the caudate to putamen from DaTscan imaging analysis. These seven SVAs also demonstrated regulatory properties as they were associated with differential gene expression in whole blood RNA sequencing data.Conclusion: This study highlights the importance of addressing variation of SVAs and potentially other types of retrotransposons in PD genetics, furthermore these SVA elements should be considered as regulatory domains that could play a role in disease progression.

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Differential gene expression in the interactome of the Human Dopamine transporter in the context of Parkinson’s disease

10.1101/2020.10.12.336388 ◽

2020 ◽

Author(s):

Roberto Navarro Quiroz ◽

Ana Ligia Scott ◽

Eric Allison Philot ◽

Linda Atencio ◽

Cecilia Fernandez Ponce ◽

...

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopamine Transporter ◽

Differential Gene Expression ◽

Systematic Effect ◽

Negative Change ◽

Internalization Process ◽

Differential Gene ◽

Main Regulator

AbstractBackgroundThe human dopamine transporter is the main regulator of dopamine tone and an intricate network exists to regulate the expression, conformation, and kinetics of the hDAT. hDAT dysfunction is directly related to Parkinson’s disease. The objective of this work is to evaluate the differential gene expression in the interactome of the Dopamine transporter in the context of Parkinson’s disease.MethodsTo do this, we evaluated hDAT interaction data in string-db, mint.bio, IntAct, reactome, hprd and BioGRID, subsequently, data was obtained from the differential gene expression of mRNA and miRNAs for this hDAT interactome in the context of PD.ResultsThe analysis of the differential expression changes of genes of the hDAT interactome in tissues of patients with PD compared with tissues of individuals without PD, allowed to identify an expression pattern of 32 components of the hDAT interactome, of which 31 presented a negative change proportion in PD.ConclusionsWe found a total of 90 miRNAs that could regulate the expression of 27 components of the hDAT interactome, at the same time, 39 components of the hDAT interactome may participate in 40 metabolic pathways. Together, these findings show a systematic effect on the hDAT-mediated dopamine internalization process in patients with Parkinson’s, which would contribute to a greater susceptibility to neuronal oxidative stress in PD patients.

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