Fighting polyglutamine disease by wrestling with SUMO.

Spinobulbar muscular atrophy (SBMA) is an X-linked disease characterized by degeneration of motor neurons, muscle atrophy, and progressive weakness. It is caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR), a transcription factor that is activated upon hormone binding. The polyQ expansion in AR causes it to form intracellular aggregates and impairs transcriptional activity. Intriguingly, SUMOylation (where SUMO indicates small ubiquitin-like modifier) of AR inhibits its transcriptional activity and reduces aggregation of the polyQ form of this protein, but it is unclear whether SUMOylation plays a pathogenic or protective role in SBMA. In this issue of the JCI, Chua et al. address this question by generating knockin mice in which the native AR is replaced by either a polyQ AR or a polyQ AR lacking the two lysine residues that are SUMOylated. The results from this study demonstrate that inhibiting SUMOylation of polyQ AR restores much of its transcriptional activity and prevents many (but not all) SBMA-associated symptoms in this mouse model.