How does loss of striatal projection neurons contribute to Huntington disease symptoms?

The pathology of Huntington disease is fundamentally linked to the degeneration and death of a specific population of projection neurons within the striatum, a key component of the basal ganglia.12

In the healthy brain, the basal ganglia function to refine motor signals by amplifying desired actions and suppressing unwanted ones. The loss of striatal projection neurons disrupts this delicate balance, altering the firing rates and patterns across the basal ganglia's parallel pathways. Because these neurons are essential for the suppression of involuntary movements, their decline leads to hyperkinesia—the hallmark symptom of Huntington disease characterized by random, uncontrollable, and often violent jerking or writhing movements known as chorea.312

Furthermore, because the basal ganglia are involved in both motor and cognitive circuits, the loss of these neurons contributes to widespread dysfunction, including progressive cognitive decline, memory loss, and neuropsychiatric symptoms such as apathy and irritability. The severity of these symptoms is directly tied to the underlying neuronal loss and the resulting disruption of the brain's ability to select and execute appropriate actions.12