Abnormal cortical development sets the stage in Huntington disease

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Huntington disease (HD) is a genetic disorder caused by CAG repeat expansion in the HTT gene.
• The HTT protein is vital for neuronal growth and intracellular transport.
• Early neurodevelopmental abnormalities are observed in HD, even before clinical symptoms manifest.

Purpose of the Study:

• To review the role of HTT and the impact of its mutation (mHTT) during neurodevelopment in HD.
• To examine the specific contribution of the cerebral cortex to HD neuropathology.
• To identify potential therapeutic intervention windows during early development.

Main Methods:

• Review of extensive research spanning nearly 25 years.
• Integration of in vitro and in vivo studies.
• Analysis of human fetal samples, cell, and animal models.

Main Results:

• Neurodevelopment is significantly altered in HD, with detectable abnormalities during the presymptomatic phase.
• Mutation carriers may exhibit subtle cognitive, psychiatric, or motor deficits years before diagnosis.
• Despite lifelong presence of mHTT, a long asymptomatic period is typical in HD.

Conclusions:

• Early developmental processes in HD are critical for understanding neuropathology.
• Identifying therapeutic targets during neurodevelopment could extend the presymptomatic phase.
• Interventions during developmental plasticity may allow the brain to compensate for errors, delaying neurodegeneration.