Development-related gene expression disruption in the human midcingulate cortex in Huntington's disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is linked to mood symptoms, often associated with anterior cingulate cortex atrophy.
• The specific role of the midcingulate cortex (MCC) in HD pathophysiology remains unclear.

Purpose of the Study:

• To investigate the transcriptomic changes in the MCC of individuals with Huntington's disease.
• To identify molecular pathways and gene expression alterations in the HD MCC.

Main Methods:

• Utilized mRNA sequencing to analyze the MCC transcriptome in 14 HD patients.
• Validated differentially expressed genes using NanoString analysis.
• Performed protein-protein interaction, gene ontology, and cell-type enrichment analyses.

Main Results:

• Identified differential expression of 223 genes in the HD MCC, including developmental and noncoding genes.
• Found dysregulated pathways related to embryonic development, organogenesis, epigenetic modification, and motor system development.
• Observed misexpressed genes linked to limb, muscle, and motor neuron development in the motor symptom cohort.

Conclusions:

• Mutant huntingtin may disrupt developmental processes in the MCC via aberrant WNT, REST, and transcription factor signaling.
• These alterations suggest a developmentally associated transcriptional signature in the adult HD MCC.
• This signature may contribute to altered MCC motor circuitry and neuronal maturation in Huntington's disease.