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Mouse models to interrogate the developmental pathogenesis of Huntington's disease.
Yagiz M Altun1,2, Siyu Yan1,2, Kevin Zheng1,2
1Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
Journal of Huntington'S Disease
|January 8, 2026
Summary
Huntington's disease (HD) involves early brain development issues, not just late-onset symptoms. Mouse models reveal developmental abnormalities and glial dysfunction that may prime the brain for later neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Huntington's disease (HD) is traditionally considered a late-onset neurodegenerative disorder.
- Emerging evidence indicates that mutant huntingtin (mHTT) impacts early brain development, preceding clinical symptoms by decades.
- Understanding these early developmental effects is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To review how various Huntington's disease mouse models illuminate developmental abnormalities and early pathogenic processes.
- To explore the role of wild-type huntingtin (HTT) and mutant huntingtin (mHTT) stoichiometry in neurodevelopment.
- To identify potential early therapeutic windows and biomarkers for HD.
Main Methods:
- Analysis of diverse Huntington's disease mouse models, including full-length transgenic, truncated fragment, knock-in, and loss-of-function models.
- Examination of developmental abnormalities such as glial dysmaturation, synaptic deficits, and neural progenitor cell disruptions.
- Investigation of early pathogenic and homeostatic processes in the developing brain.
Main Results:
- Different HD mouse models exhibit distinct but converging developmental abnormalities, including glial dysmaturation, synaptic deficits, and myelination defects.
- Knock-in models show CAG-length-dependent disruptions in neural progenitor cells, synaptic formation, and cortical plasticity.
- Loss-of-function models highlight the role of wild-type HTT in neural patterning and germ layer specification.
Conclusions:
- HD has a significant developmental dimension, with early-life circuit miswiring and glial dysfunction potentially predisposing the brain to later neurodegeneration.
- These early disruptions are critical for understanding HD pathogenesis and developing disease-modifying treatments.
- Identifying early therapeutic targets and biomarkers is essential for preventing or delaying HD onset.
