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<p>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 <i>HTT</i> 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 <i>Htt</i>. Bdnf was the most probable upstream regulator of these genes. <i>Smarca4</i>, the Bdnf-regulator, was similarly expressed to wild-type <i>Htt</i> in the control brain; however, this was not observed in HD, implying a possible involvement of <i>Smarca4</i> in glutamate excitotoxicity in HD. <i>Lhx6</i>, 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, <i>Fcho1</i>, was lost <i>in</i> connection involving <i>Lhx6</i> and mitochondrial gene clusters. Loss of <i>Smarca4</i>, <i>Lhx6</i>, and <i>Fcho1</i> in co-expression may contribute to spatiotemporally specific neuronal loss in HD.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Yuko Okamura-Oho,
  • Kazuro Shimokawa,
  • Satoshi Oota,
  • Atsushi Yoshiki,
  • Masahiko Morita,
  • Masaomi Nishimura,
  • Sakiko Nakamura,
  • Yuki Tsujimura,
  • Shumpei Ishikawa,
  • Hideo Yokota

摘要

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.