Spinal and bulbar muscular atrophy: a motoneuron or muscle disease?

Abstract

Kennedy disease (KD, or spinal and bulbar muscular atrophy) is caused by a CAG/polyglutamine expansion in the androgen receptor (AR) gene. Both motoneurons and muscles are affected by KD, but where mutant ARs act to initiate this disease is not clear. We discuss recent insights into this disease with two main themes. (1) KD is androgen-dependent, suggesting that blocking androgen action may be an effective treatment. (2) Androgens may trigger KD by acting in muscles, which indirectly affects the motoneurons, suggesting that blocking AR function in muscles may rescue motoneurons from disease and provide an effective treatment. Future research will provide a better understanding of how androgens trigger KD and the relative contributions of motoneurons versus muscles in this disease.

Figure 1

Schematic showing two possible sites (motoneurons or muscle fibers) where mutant ARs might act to trigger Kennedy Disease (KD). Because motoneurons and muscle fibers each express ARs, each represents candidate sites for triggering KD. Mutant ARs could cause the same distal axonopathy (depicted by dashed lines for some motor axons and their terminals) by directly impairing the function of motoneurons or muscle fibers. In one case, distal axonopathy is caused by altered anterograde signaling in the affected motoneuron (shown in red in left panel) while in the other case, axonopathy is induced indirectly via changes in retrograde signals from the affected muscle fibers (shown in red in right panel). Based on several mouse models of KD, axonopathy occurs early in the disease process and may involve a perturbation in motoneuronal axonal transport. As this disease progresses, such axonopathy leads to functionally denervated muscle fibers, triggering muscle atrophy and motoneuronal cell death, two key pathological features of KD. It is also possible that AR acts in both cell types to induce the full complement of disease symptoms underlying KD and that AR action at both sites are critically involved. Studies are needed to fully discern the role of ARs in motoneurons and muscle fibers in causing KD.