Have We Been Thinking About the Causes of Huntington Disease All Wrong?

Since the discovery of the CAG repeat expansion in huntingtin and its association with Huntington disease (HD), researchers have looked for answers to three critical questions. First, how do the inherited alleles lead to the cell toxicity associated with the disease's symptoms, which include uncontrolled movements and cognitive deterioration? Second, why is the toxicity specific to certain cell types? Finally, why does HD stay latent for years before manifesting? To answer these questions, researchers have now used single-cell measurement of the CAG repeat, paired with genome-wide RNA expression, in patients at different clinical HD stages and in healthy controls.

Somatic expansion of the genetic repeat drove pathological changes in neurons …