One of the great mysteries of Huntington disease (HD) is its adult onset. HD is caused by a CAG repeat expansion in the HTT gene, which encodes a protein (HTT) that is crucial for intracellular transport and neuronal growth, so one would expect development to be altered in some way. Human fetal samples, cell and animal model studies have shown that neurodevelopment is indeed altered in HD. Structural and functional abnormalities can be detected during the presymptomatic phase, and mutation carriers may display subtle cognitive deficits, psychiatric disturbances, or motor impairments years before clinical diagnosis. However, despite these early developmental alterations and the lifelong presence of mutant huntingtin (mHTT), HD carriers typically experience a long asymptomatic period. In this review, we provide an overview of the functions of HTT and the dysfunctions caused by mHTT or HTT loss during development, from gastrulation to neurulation, and examine the specific contribution of the cerebral cortex in HD. Drawing on nearly 25 years of research, we integrate studies ranging from in vitro to in vivo studies, highlighting the molecular mechanisms that contribute to HD neuropathology. Understanding these early developmental processes may define a window for therapeutic intervention, a period of plasticity during which the brain may still correct or compensate for developmental errors. This could strengthen the foundations to extend the presymptomatic phase and delay neurodegeneration.
Degennaro et al. (Fri,) studied this question.