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Related Concept Videos

Huntington Disease l: Introduction01:21

Huntington Disease l: Introduction

Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...

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Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's

Lulin Huang1,2, Li Fang2, Qian Liu2

  • 1The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, PR China.

Genes & Diseases
|February 28, 2022
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Summary

Huntington's disease (HD) research in knock-in mice links CAG repeat length to specific behaviors and gene expression changes. This study reveals correlations crucial for understanding HD and developing new treatments.

Keywords:
BehaviorsCAG repeatHuntington's diseaseMiceSingle-cell RNA sequencingSmall chemicalsStriatumTranscriptome

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Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Huntington's disease (HD) is a genetic neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (HTT) gene.
  • Knock-in mouse models carrying expanded CAG repeats in the Htt gene recapitulate HD phenotypes, showing age- and genotype-dependent molecular network dysregulation.
  • Previous research identified behavioral signatures for HD in these mice but lacked integrated analysis correlating specific behaviors with CAG repeat length.

Purpose of the Study:

  • To conduct an integrated analysis correlating behavioral features with genotypes (CAG repeat expansions) in Htt CAG-knock-in mice.
  • To investigate the landscape of behavioral features and gene expression correlations.
  • To identify potential therapeutic targets for Huntington's disease.

Main Methods:

  • Analysis of 445 mRNA and 445 microRNA samples from Htt CAG-knock-in mice.
  • Comprehensive behavioral analysis using 396 PhenoCube and 111 NeuroCube behaviors.
  • Integration of gene expression data with behavioral features and single-cell/spatial transcriptomics.

Main Results:

  • Identification of 37 behavioral features significantly associated with CAG repeat length, including step count and hind limb stand duration.
  • Association of these behavioral features with gene coexpression networks involved in neuronal dysfunction, supported by striatal single-cell and brain spatial gene expression data.
  • Discovery of 15 chemicals, primarily dopamine and serotonin receptor modulators, showing significant responses related to genes enriched in behavioral features.

Conclusions:

  • Abnormal neuronal signal transduction in the striatum is a key contributor to HD-related behaviors.
  • The identified correlations provide a rich dataset for understanding HD pathogenesis.
  • Findings offer valuable insights for future pharmacotherapeutic interventions for Huntington's disease.