The breaking point where repeat expansion triggers neuronal collapse in Huntington's disease

Abstract

Somatic CAG expansion drives neuronal loss in Huntington's disease (HD), but how expansion results in pathogenesis has remained unclear. Handsaker et al.¹ use single-cell RNA and repeat length sequencing to reveal a phased model of expansion and toxicity, highlighting a critical tipping point beyond 150 CAG repeats where neuronal identity collapses and cells die.

Figure 1

The phased model of CAG expansion and neuronal collapse in Huntington’s disease (A) Somatic expansion of the HTT CAG repeat progresses through distinct phases over a neuron’s lifetime. In phase A (40–80 CAGs), neurons remain stable with slow expansion. Phase B (80–150 CAGs) marks a rapid acceleration in expansion rate. Phase C (150+ CAGs) sees progressive transcriptional dysregulation, leading to the loss of neuronal identity. Phase D (350+ CAGs) is characterized by de-repression of embryonic and non-neuronal genes, triggering crisis. Phase E marks neuronal collapse and cell death. iSPNs are the most vulnerable to this process, which potentially explains their early degeneration in HD. This phased model provides a framework for understanding HD pathogenesis and therapeutic intervention. (B) The distribution of CAG repeat lengths across individual medium spiny neurons (MSNs, adapted from Handsaker et al.¹) reflects the heterogeneity of somatic expansion at the time of death. This snapshot captures neurons at different points in the expansion process. MSNs spend over 96% of their life in phase A, where CAG expansion is glacially slow, before accelerating in phase B. A fraction of MSNs have exceeded the critical threshold (∼150 CAGs) and are in advanced stages of transcriptional collapse. However, this phase is rapid, and these neurons do not persist for long.