, 2008). The presence of polyQ-1C2-positive inclusions suggests that two mechanisms might contribute to disease; a toxic RNA encoded by

one strand and a polyQ peptide encoded by the other ( Figure 1). In an attempt to clarify the molecular source of pathogenicity in HDL2, Yang and colleagues (as detailed in this issue of Neuron) engineered a series of transgenic mice expressing Sirolimus mw human JPH3 mutant alleles. Using bacterial artificial chromosomes (BACs), an approached pioneered by the Yang group for the study of HD, Wilburn et al. (2011) generated transgenic mice carrying 165 kb from the JPH3 locus with ∼120 CAG repeats. These mutant JPH3 BAC mice presented with several key features found in HDL2 patients. Among these are an age-dependent motor deficit, forebrain atrophy, and the presence of nuclear inclusions positive for ubiquitin and reactive with two polyQ antibodies, including

1C2. At a molecular level, Yang and colleagues provide evidence for a novel promoter that drives expression of a polyQ-encoding transcript Sorafenib concentration from the DNA strand in the antisense orientation to JPH3. Importantly, Wilburn et al. provide biochemical evidence that mutant BAC-JPH3 brains express insoluble polyQ peptides of a size range that would be expected to be encoded by the JPH3 CAG antisense strand of the BAC transgene. However, the nuclear TCL inclusions in the mutant BAC-JPH3

mice are also positive for RNA from the sense CUG strand. Given this finding, which of the two transcripts is the pathogenic species in the BAC-JPH3 mice? Does disease progression require functional expression of both transcripts? To address the extent to which the CAG-polyQ-encoding antisense transcript contributes to pathogenesis, Wilburn et al. developed a second version of an expanded CAG repeat BAC-JPH3 transgenic mouse, designated BAC-HDL2-STOP. In this mouse, exon 1 of the JPH3 transgene was replaced with a previously well-characterized transcription STOP sequence such that expression of the JPH3 CUG sense strand is selectively silenced while expression of the antisense CAG transcript remains intact. By behavioral and neurological measures, the BAC-HDL2-STOP mice expressing only the CAG antisense transcript develop motor deficits and degenerative pathology very similar to that seen in the original BAC-JPH3 mice expressing both transcripts. Although the extent to which the JPH3 sense CUG transcript contributes to disease was not assessed directly, these results provide strong evidence that the CAG antisense transcript is very pathogenic and a prominent contributor to disease progression in this mouse model of HDL2. In a final series of studies, Wilburn et al. provide evidence that, like other polyQ disorders (e.g.