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

Huntington's disease (HD) patients with anterior cingulate cortex atrophy typically exhibit mood symptomatology. However, the midcingulate cortex's (MCC) role in HD is poorly understood. mRNA sequencing was utilized to examine the MCC transcriptome in HD, and differentially expressed transcripts were validated by NanoString analysis. Transcriptomic analysis of 14 HD patients exhibiting mood, motor, or mixed symptoms revealed differential expression of 223 genes, including several homeo-domain, developmental, and noncoding genes in the MCC. Protein-protein interaction, gene ontology, and cell-type enrichment analyses identified dysregulated pathways in the adult MCC involved in processes linked to embryonic development and organogenesis, epigenetic modification, transcription regulation, neuronal differentiation, and motor system development. Key findings include misexpressed genes associated with limb, muscle and motor neuron development in the motor cohort. These alterations suggest that mutant huntingtin may influence developmental processes via aberrant WNT (Wingless), REST (RE1-silencing transcription factor), and transcription factor signaling, potentially affecting MCC motor function circuitry and neuronal maturation. This study indicates a developmentally associated transcriptional signature in the adult HD MCC that may contribute to altered neuronal function.