Abstract
Huntington's and Parkinson's Diseases (HD and PD) are neurodegenerative disorders that share some pathological features but are disparate in others. For example, while both diseases are marked by aberrant protein aggregation in the brain, the specific proteins that aggregate and types of neurons affected differ. A better understanding of the molecular similarities and differences between these two diseases may lead to a more complete mechanistic picture of both the individual diseases and the neurodegenerative process in general. We sought to characterize the common transcriptional signature of HD and PD as well as genes uniquely implicated in each of these diseases using mRNA-Seq data from post mortem human brains in comparison to neuropathologically normal controls. The enriched biological pathways implicated by HD differentially expressed genes show remarkable consistency with those for PD differentially expressed genes and implicate the common biological processes of neuroinflammation, apoptosis, transcriptional dysregulation, and neuron-associated functions. Comparison of the differentially expressed (DE) genes highlights a set of consistently altered genes that span both diseases. In particular, processes involving nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and transcription factor cAMP response element-binding protein (CREB) are the most prominent among the genes common to HD and PD. When the combined HD and PD data are compared to controls, relatively few additional biological processes emerge as significantly enriched, suggesting that most pathways are independently seen within each disorder. Despite showing comparable numbers of DE genes, DE genes unique to HD are enriched in far more coherent biological processes than the DE genes unique to PD, suggesting that PD may represent a more heterogeneous disorder. The complexity of the biological processes implicated by this analysis provides impetus for the development of better experimental models to validate the results.
Highlights
Transcriptional dysregulation has been observed in both Huntington’s disease (HD) and Parkinson’s disease (PD) (Cha, 2007; Elstner et al, 2011)
Gene set enrichment analysis of MsigDB C2 gene sets identified 226, 199, and 250 gene sets significantly enriched at q-value < 0.05 for HD, PD, and neurodegenerative disease (ND), respectively
There was a high degree of overlap between the significantly enriched gene sets of HD and PD. 145 gene sets were significantly enriched in both differentially expressed (DE) gene lists, while 81 and 54 gene sets were uniquely significant in HD and PD, respectively
Summary
Transcriptional dysregulation has been observed in both Huntington’s disease (HD) and Parkinson’s disease (PD) (Cha, 2007; Elstner et al, 2011). A systematic comparison of the transcriptional signatures of HD and PD has not been performed to date, and those genes and biological processes common to both diseases, if any, remain to be determined. To address this question, we sought to identify genes that are consistently differentially expressed (DE) in the post-mortem brains of HD and PD human subjects compared to neuropathologically normal control brains using mRNA-Seq. We hypothesize that common altered genes and pathways in HD and PD will elucidate the mechanistic underpinnings of the neurodegenerative process. DE genes are determined using a tailored form of logistic regression as previously described (Choi et al, 2017), which improves control of type I errors when compared to negative binomial based DE detection techniques
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