Layer 5a Corticostriatal Projection Neurons are Selectively Vulnerable in Huntington's Disease.

The properties of the cell types that are most vulnerable in the Huntington's disease (HD) cortex, the nature of somatic CAG expansion of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here we have employed serial fluorescence activated nuclear sorting (sFANS), deep molecular profiling, and single nucleus RNA sequencing (snRNAseq) to demonstrate that layer 5a pyramidal neurons are selectively vulnerable in primary motor cortex and other cortical areas. Extensive somatic mHTT -CAG expansion occurs in vulnerable layer 5a pyramidal cells, and in Betz cells, layer 6a, layer 6b neurons that are not lost in HD. Retrograde tracing experiments in the macaque brain identify the vulnerable layer 5a neurons as corticostriatal pyramidal cells. Our data establish that mHTT -CAG expansion is not sufficient for cell loss in the cerebral cortex of HD, and suggest that cortico-striatal disconnection in early-stage HD patients may play an important role in neurodegeneration.