Kavli Affiliate: Nathaniel Heintz
| Authors: Christina Pressl, Kert Mätlik, Laura Kus, Paul Darnell, Ji-Dung Luo, Matthew R Paul, Alison R Weiss, William Liguore, Thomas Carroll, David A Davis, Jodi McBride and Nathaniel Heintz
| Summary:
The properties of the cell types that are most vulnerable in Huntington’s disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here we 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 of HD donors. Extensive mHTT-CAG expansions occur 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 macaque brains 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, suggesting that cortico-striatal disconnection in HD patients may play an important role in neurodegeneration.