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dc.contributor.authorSanchez Nido, Gonzalo
dc.contributor.authorDick, Fiona
dc.contributor.authorToker, Lilah
dc.contributor.authorPetersen, Kjell
dc.contributor.authorAlves, Guido Werner
dc.contributor.authorTysnes, Ole-Bjørn
dc.contributor.authorJonassen, Inge
dc.contributor.authorHaugarvoll, Kristoffer
dc.contributor.authorTzoulis, Charalampos
dc.date.accessioned2021-04-27T11:19:43Z
dc.date.available2021-04-27T11:19:43Z
dc.date.created2020-11-12T10:22:36Z
dc.date.issued2020-04-21
dc.PublishedActa neuropathologica communications. 2020, 8 .
dc.identifier.issn2051-5960
dc.identifier.urihttps://hdl.handle.net/11250/2739900
dc.description.abstractThe etiology of Parkinson’s disease is largely unknown. Genome-wide transcriptomic studies in bulk brain tissue have identified several molecular signatures associated with the disease. While these studies have the potential to shed light into the pathogenesis of Parkinson’s disease, they are also limited by two major confounders: RNA post-mortem degradation and heterogeneous cell type composition of bulk tissue samples. We performed RNA sequencing following ribosomal RNA depletion in the prefrontal cortex of 49 individuals from two independent case-control cohorts. Using cell type specific markers, we estimated the cell type composition for each sample and included this in our analysis models to compensate for the variation in cell type proportions. Ribosomal RNA depletion followed by capture by random primers resulted in substantially more even transcript coverage, compared to poly(A) capture, in post-mortem tissue. Moreover, we show that cell type composition is a major confounder of differential gene expression analysis in the Parkinson’s disease brain. Accounting for cell type proportions attenuated numerous transcriptomic signatures that have been previously associated with Parkinson’s disease, including vesicle trafficking, synaptic transmission, immune and mitochondrial function. Conversely, pathways related to endoplasmic reticulum, lipid oxidation and unfolded protein response were strengthened and surface as the top differential gene expression signatures in the Parkinson’s disease prefrontal cortex. Our results indicate that differential gene expression signatures in Parkinson’s disease bulk brain tissue are significantly confounded by underlying differences in cell type composition. Modeling cell type heterogeneity is crucial in order to unveil transcriptomic signatures that represent regulatory changes in the Parkinson’s disease brain and are, therefore, more likely to be associated with underlying disease mechanisms.en_US
dc.language.isoengen_US
dc.publisherBMCen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleCommon gene expression signatures in Parkinson’s disease are driven by changes in cell compositionen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright The Author(s) 2020en_US
dc.source.articlenumber55en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1
dc.identifier.doi10.1186/s40478-020-00932-7
dc.identifier.cristin1847297
dc.source.journalActa neuropathologica communicationsen_US
dc.source.408
dc.source.pagenumber1-14en_US
dc.relation.projectNorges forskningsråd: 288164en_US
dc.relation.projectBergens forskningsstiftelse: BFS2017REK05en_US
dc.identifier.citationActa Neuropathologica Communications volume. 2020, 8, 55en_US
dc.source.volume8en_US


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