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Huntington's as a developmental disorder: Molecular and neuropathologic considerations
Journal article   Peer reviewed

Huntington's as a developmental disorder: Molecular and neuropathologic considerations

Mallory R Shin and Marco M Hefti
Journal of Huntington's disease, Vol.15(2), pp.226-234
05/2026
DOI: 10.1177/18796397251395783
PMID: 41252373

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Abstract

Huntington's disease (HD) is classically characterized as a late-onset neurodegenerative disorder of adulthood caused by CAG expansion in the gene. However, mounting evidence from both human and experimental studies suggests that both wild-type and mutant huntingtin play important roles during brain development. In this review, we examine the developmental functions of huntingtin, including its role in neuronal migration, synaptogenesis, suppression of apoptosis, mitotic spindle orientation, and transcriptional regulation. We also discuss how mutant may act through both loss- and gain-of-function mechanisms during early brain development. Comparative evolutionary analysis suggests that is highly conserved and that the emergence of the N-terminal polyglutamine tract may have conferred developmental advantages in organisms with more complex nervous systems. Interestingly, studies in pre-symptomatic human carriers and mouse models have identified potential early-life cognitive benefits associated with moderate CAG expansion, raising the possibility of antagonistic pleiotropy. Understanding huntingtin's dual function in neurodevelopment and degeneration is essential in gaining insights into the earliest stages of HD pathogenesis, long before clinical onset.
 Apoptosis mouse models REST/NRSF development neurodegeneration HTT pediatric neurogenetics Huntington's disease antagonistic pleiotropy neurodevelopment N-cadherin huntingtin neuronal migration developmental neuroscience synaptogenesis pre-symptomatic

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