Topological modeling of gene expression in the brain with Huntington's disease reveals selective disruption of co-expression network.

We applied transcriptome tomography to create a whole-brain model of early-stage Huntington's disease (HD) in R6/2 mice, which ubiquitously express truncated human mutant HTT containing approximately 150 CAG repeats. Medium spiny neuron (MSN)-related genes showed abnormal expression in the HD brain, in terms of expression similarity to wild-type Htt. Bdnf was the most probable upstream regulator of these genes. Smarca4, the Bdnf-regulator, was similarly expressed to wild-type Htt in the control brain; however, this was not observed in HD, implying a possible involvement of Smarca4 in glutamate excitotoxicity in HD. Lhx6, a master gene for MSN-related pathway development ordinarily conserved postnatally and in adulthood, was lost in the HD co-expression network. And a network hub node, Fcho1, was lost in connection involving Lhx6 and mitochondrial gene clusters. Loss of Smarca4, Lhx6, and Fcho1 in co-expression may contribute to spatiotemporally specific neuronal loss in HD.