Background In Huntington’s disease (HD) mutant HTT is ubiquitously expressed and has systemic effects. Availability of brain tissue is limited and postmortem samples are from advanced disease. Blood, however, is readily available, can be studied longitudinally, and contains cells shown to be dysfunctional in HD.
There is marked transcriptional dysregulation in HD brain. Differential expression has also been described in muscle and blood, though changes are inconsistent and poorly replicate CNS findings, questioning their biological relevance.
Aims and methods We used RNA-Seq to analyse the transcriptome of whole blood in two separate cohorts comprising a total of 186 HD subjects and 49 controls.
Results Though individual transcripts were not significantly differentially expressed in either cohort, gene set enrichment analysis applied to publicly-available pathway databases and HD and control brain co-expression modules showed a significant overlap in dysregulated pathways between the cohorts. In particular, immune pathways were upregulated in both cohorts. Notably, modules previously shown to be significantly dysregulated in HD caudate were also significantly dysregulated in the same direction in both blood cohorts, as well as an independent cortex expression dataset. In addition, we identified overlapping immune upregulation in HD and Alzheimer’s disease (AD), suggesting these two distinct neurodegenerative diseases share some common pathogenic mechanisms.
Conclusions We have therefore shown that transcriptional dysregulation in key pathways in HD blood parallels changes found in brain. This overlaps with the transcriptional signature in AD, raising the potential for shared therapeutic approaches. Furthermore, analysing pathways may overcome the cellular and technical heterogeneity that prevent the blood transcriptome replicating changes in the brain transcriptome at a single-gene level.
- Alzheimer’s disease
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