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

Mallory R Shin; Marco M Hefti

doi:10.1177/18796397251395783

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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

11/18/2025

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

Details

Title: Subtitle: Huntington's as a developmental disorder: Molecular and neuropathologic considerations
Creators: Mallory R Shin - University of Iowa
Marco M Hefti - University of Iowa
Resource Type: Journal article
Publication Details: Journal of Huntington's disease
DOI: 10.1177/18796397251395783
PMID: 41252373
NLM abbreviation: J Huntingtons Dis
ISSN: 1879-6397
eISSN: 1879-6400
Publisher: Sage
Grant note: National Institute of Neurological Disorders and Stroke: R01 NS136448 Roy J. Carver FoundationUniversity of Iowa Graduate CollegeIowa Neuroscience Institute
This work was supported by the NIH/NINDS (R01 NS136448 to MMH), the Roy J. Carver Foundation, and the Iowa Neuroscience Institute (both to MMH). Additional support was provided by the University of Iowa Graduate College to MRS.
Language: English
Electronic publication date: 11/18/2025
Academic Unit: Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute
Record Identifier: 9985033764102771

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