Schematics illustrating the two-hit hypothesis of neuropathogenesis in conditional models of HD. Our current analyses of the striatal model and our previous study of the cortical and pan-neuronal model of HD have shown that behavioral deficits and robust cortical and striatal neuropathology are observed only when mhtt-exon1 is broadly expressed in the brain (pan-neuronal model). When mhtt-exon1 only is expressed in one of the known vulnerable neuronal populations, CPNs (cortical model) or striatal MSNs (striatal model), significant motor deficits or robust gliosis and degenerative changes did not occur despite cell-autonomous accumulation of mhtt aggregates. Thus, these findings rule out the cell-autonomous model which suggests expression of mhtt in the vulnerable neurons alone is sufficient to elicit robust neuropathology in that neuron (A). Since in both the cortical model  and in the striatal model, cell-autonomous expression of mhtt did exhibit evidence of neuronal dysfunction (i.e. degenerating lysosomes in the cortical model and electrophysiological changes in striatal model), the findings also suggest a pure cell-cell interaction model (B) is also unlikely. Thus, our current data favor the two-hit hypothesis (C), which suggests both cell-autonomous toxicity and pathological cell-cell interaction synergistically contribute to neuropathogenesis of the vulnerable cortical and striatal neurons.