Background While the genetic cause of Huntington’s Disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. We previously showed that HD specific functional signatures in human blood adequately represent signatures in human brain and hence could be used as biomarkers.
Aims Since potential drugs are first screened in rodent models, we aimed to determine whether the previously identified human signatures are also present in the YAC128 HD mouse model.
Methods We isolated and sequenced RNA from blood collected at 12 and 20 months and four end stage brain regions from 8 YAC128 mice and 8 wild type mice. Differential gene expression analysis was applied to identify genes differentially expressed (DE) and weighted gene coexpression network analysis to identify groups of genes strongly co-expressed (modules). To technically validate RNAseq results, qPCR and western blot were performed.
Results RNAseq data was validated by qPCR and western blot, confirming our gene expression analysis. Early stage blood displayed modest changes related to immune response(7 DE genes; 2 modules). At 20 months, an intermediate pathology was detected in blood (162 DE genes; 22 modules), including additional processes such as autophagy, protein transport and modification and DNA repair. In terms of differential gene expression, cortex and brainstem exhibited a mild phenotype (33 and 60 DE genes respectively), while cerebellum and striatum showed intermediate to moderate changes (145 and 101 DE genes respectively). Cerebellum and striatum showed respectively 26 and 11 modules significantly associated with HD, while this was 16 for cortex and 14 for brainstem. Representative annotations presented by all four brain regions were immune response, DNA repair, protein transport, chromatin modification and myelination.
Conclusions Similar modules were present in blood and brain gene expression data from mouse and human related to immune response, protein transport and chromatin remodelling. Our next step is to statistically determine similarities between blood and brain signatures in mouse with a computational randomization experiment.
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