Neuromuscular junction (purple) in a Drosophila model of SBMA, with active zones shown in green. Image courtesy of J. P. Taylor.
Spinobulbar muscular atrophy (SBMA) is one of nine polyglutamine (polyQ) diseases, which are collectively the most common inherited neurodegenerative disorders. PolyQ diseases involve expansion of CAG repeats in specific regions of exonic DNA; in SBMA, these mutations occur in the gene encoding the androgen receptor (AR). How expanded CAG repeats induce neurodegeneration in polyQ diseases has been unclear. Nedelsky et al. now show using a Drosophila model of SBMA that the disease is caused by an imbalance in the multiple native functions of the AR. A genetic screen for disease modifiers also reveals that, in addition to the expanded glutamine tract, the AF-2 domain of the AR protein is required for neuropathology. These findings are complemented by a report by Duvick et al., who show in mice that the pathology of another polyQ disease known as spinocerebellar ataxia type 1 is caused by multiple domains and altered native functions of the ATXNI protein. These two studies clarify the mechanisms by which multifunctional proteins induce pathology in polyQ diseases.
