8 research outputs found
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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
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
-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
-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
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Selective vulnerability of layer 5a corticostriatal neurons in Huntington's disease
The properties of the cell types that are selectively 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 (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex