The study by Pressl et al. investigates the selective vulnerability of layer 5a corticostriatal neurons in Huntington's disease (HD). Using serial fluorescence-activated nuclear sorting (sFANS) and single-nucleus RNA sequencing (snRNA-seq), the authors reveal that L5a pyramidal neurons are lost early in HD progression. Molecular profiling data show extensive somatic CAG expansion in both vulnerable L5a neurons and resilient Betz cells, layers 6a and 6b neurons. Retrograde tracing experiments in macaque brains confirm that L5a neurons are corticostriatal pyramidal cells. The findings suggest that enhanced somatic *mHTT* CAG expansion and altered synaptic function together contribute to corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex. The study provides insights into the molecular pathology of HD and highlights the importance of L5a neurons in the disease process.The study by Pressl et al. investigates the selective vulnerability of layer 5a corticostriatal neurons in Huntington's disease (HD). Using serial fluorescence-activated nuclear sorting (sFANS) and single-nucleus RNA sequencing (snRNA-seq), the authors reveal that L5a pyramidal neurons are lost early in HD progression. Molecular profiling data show extensive somatic CAG expansion in both vulnerable L5a neurons and resilient Betz cells, layers 6a and 6b neurons. Retrograde tracing experiments in macaque brains confirm that L5a neurons are corticostriatal pyramidal cells. The findings suggest that enhanced somatic *mHTT* CAG expansion and altered synaptic function together contribute to corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex. The study provides insights into the molecular pathology of HD and highlights the importance of L5a neurons in the disease process.