Common disease signatures from gene expression analysis in Huntington’s disease human blood and brain

Abstract

BackgroundHuntington’s disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and impossible to perform longitudinal studies. However, peripheral pathology in HD suggests that it is possible to study the disease using peripheral tissue as a monitoring tool for disease progression and/or efficacy of novel therapies. In this study, we investigated if blood can be used to monitor disease severity and progression in brain. Since previous attempts using only gene expression proved unsuccessful, we compared blood and brain Huntington’s disease signatures in a functional context.MethodsMicroarray HD gene expression profiles from three brain regions were compared to the transcriptome of HD blood generated by next generation sequencing. The comparison was performed with a combination of weighted gene co-expression network analysis and literature based functional analysis (Concept Profile Analysis). Uniquely, our comparison of blood and brain datasets was not based on (the very limited) gene overlap but on the similarity between the gene annotations in four different semantic categories: “biological process”, “cellular component”, “molecular function” and “disease or syndrome”.ResultsWe identified signatures in HD blood reflecting a broad pathophysiological spectrum, including alterations in the immune response, sphingolipid biosynthetic processes, lipid transport, cell signaling, protein modification, spliceosome, RNA splicing, vesicle transport, cell signaling and synaptic transmission. Part of this spectrum was reminiscent of the brain pathology. The HD signatures in caudate nucleus and BA4 exhibited the highest similarity with blood, irrespective of the category of semantic annotations used. BA9 exhibited an intermediate similarity, while cerebellum had the least similarity. We present two signatures that were shared between blood and brain: immune response and spinocerebellar ataxias.ConclusionsOur results demonstrate that HD blood exhibits dysregulation that is similar to brain at a functional level, but not necessarily at the level of individual genes. We report two common signatures that can be used to monitor the pathology in brain of HD patients in a non-invasive manner. Our results are an exemplar of how signals in blood data can be used to represent brain disorders. Our methodology can be used to study disease specific signatures in diseases where heterogeneous tissues are involved in the pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0475-2) contains supplementary material, which is available to authorized users.

Leukocyte telomere shortening in Huntington's disease

“…There is evidence that toxic HTT aggregates are accompanied by a neuroinflammatory state characterized by activation of the microglia in the brain of HD patients [31][32][33]. Microglia activation can be observed early in pre-manifest HD, followed by the release of proinflammatory mediators.…”

Single-nucleus RNA-seq identifies Huntington disease astrocyte states

“…Whereas bulk transcriptome-wide studies have provided important insights into molecular changes in HD [1,14,15,23,29,38], bulk samples comprise a mixture of cell types, so astrocyte-specific signatures in HD may be obscured. Single cell RNA sequencing (scRNAseq) is a powerful technique to interrogate cellular heterogeneity [6,42].…”

Genetic variants in humanin nuclear isoform gene regions show no association with coronary artery disease

“…Humanin isoforms have also been studied as potential biomarkers for Alzheimer`s disease-like dementia and Hirschsprung's disease, suggesting their wider role in physiological processes [24,25]. Research on cancer subtypes, Dicer-binding genes, genomic mosaicism, extracellular RNA profiles, chromosomal rearrangements and huntingtin interactions has provided insight into networks in which humanin-like isoforms might be of importance [26][27][28][29][30][31].…”