Footprints of SBMA mice (front paws in blue and hind paws in red) show improved gait following treatment with ASC-J9 relative to vehicle.
Parents often separate siblings to break up fights. A similar approach may reduce the toxicity of diseases that involve the formation of large protein aggregates, like polyglutamine expansion disorders. Expansion of the androgen receptor polyglutamine tract is associated with spinal and bulbar muscular atrophy (SBMA or Kennedy disease), an X-linked recessive disorder that causes muscle weakness, twitching and atrophy, as well as difficulty speaking and swallowing. Yang et al. previously identified ASC-J9 in a screen for compounds that disrupt the association of androgen receptors with transcriptional coactivators. Now they report that ASC-J9 improves motor behavior in mice expressing polyglutamine-expanded androgen receptors in a recent article in Nature Medicine.
Androgen receptors are ligand-inducible transcription factors. Once bound to dihydrotestosterone, androgen receptors translocate to the nucleus and bind androgen response elements in gene promoters. There, they recruit coactivators that help induce transcription. Polyglutamine-expanded androgen receptors form nuclear inclusion bodies, protein aggregates that also contain transcriptional coactivators. These clumps of protein are toxic and may prevent normal transcription.
Dihydrotestosterone induced the transcription of a reporter containing an androgen response element in a prostate cancer cell line and in cells transfected with polyglutamine-expanded androgen receptors. The authors found reduced dihydrotestosterone-mediated transcription in cells of either type treated with ASC-J9. This treatment also reduced expression of androgen receptor protein, suggesting that ASC-J9 induces androgen receptor degradation. The androgen receptor coactivator CREB-binding protein induces expression of VEGF164 mRNA. Relative to vehicle-treated controls, ASC-J9 increased VEGF164 mRNA in cells expressing polyglutamine-expanded androgen receptors, suggesting that ASC-J9 releases CREB-binding protein from androgen receptor-containing protein aggregates.
ASC-J9 reduces androgen receptor aggregation. In cells transfected with polyglutamine-expanded androgen receptors, dihydrotestosterone induced the formation of nuclear inclusion bodies. ASC-J9 given in combination with dihydrotestosterone reduced the number of protein aggregates, the amount of androgen receptor protein localized to the nucleus and cell survival time relative to dihydrotestosterone treatment alone.
ASC-J9 ameliorated symptoms of SBMA in mice. Mice with transgenic expression of polyglutamine-expanded androgen receptors (SBMA mice) show hind-limb clasping, irregular gait and progressively worse performance on the rotarod, which tests motor coordination. ASC-J9 treatment before symptom onset at 5 weeks of age and after symptom onset at 26 weeks of age reduced hind-limb clasping, normalized gait and improved performance on the rotarod in these mice. Relative to vehicle, ASC-J9 treatment also increased the lifespan of SBMA mice. In SBMA mice, hematoxylin and eosin staining showed reduced muscle atrophy, and immunocytochemistry showed reduced nuclear localization of androgen receptors following ASC-J9 relative to vehicle treatment.
Because SBMA is an X-linked recessive disorder, most people with SBMA are men. There currently is no treatment for SBMA. Castration improves symptoms in SBMA mice, but impairs sexual function and fertility. In contrast, ASC-J9 treatment enhanced fertility in SBMA mice, suggesting that it could be a viable treatment for people with SBMA. Treatments that disrupt protein aggregates may benefit people with other polyglutamine-expansion disorders, including Huntington disease.