Shared and oppositely regulated transcriptomic signatures in Huntington's disease and brain ischemia confirm known and unveil novel potential neuroprotective genes

Abstract

Huntington's disease and subcortical vascular dementia display similar dementing features, shaped by different degrees of striatal atrophy, deep white matter degeneration and tau pathology. To investigate the hypothesis that Huntington's disease transcriptomic hallmarks may provide a window into potential protective genes upregulated during brain acute and subacute ischemia, we compared RNA sequencing signatures in the most affected brain areas of 2 widely used experimental mouse models: Huntington's disease, (R6/2, striatum and cortex and Q175, hippocampus) and brain ischemia-subcortical vascular dementia (BCCAS, striatum, cortex and hippocampus). We identified a cluster of 55 shared genes significantly differentially regulated in both models and we screened these in 2 different mouse models of Alzheimer's disease, and 96 early-onset familial and apparently sporadic small vessel ischemic disease patients. Our data support the prevalent role of transcriptional regulation upon genetic coding variability of known neuroprotective genes (Egr2, Fos, Ptgs2, Itga5, Cdkn1a, Gsn, Npas4, Btg2, Cebpb) and provide a list of potential additional ones likely implicated in different dementing disorders and worth further investigation.

Keywords: Huntington's disease (HD); Neurodegeneration; Small vessel ischemic disease (SVID); Subcortical vascular dementia (sVaD); Transcriptome.