The role of the polyglutamine tract in androgen receptor

The androgen receptor (AR) is a ligand-activated transcription factor which is responsible for the androgen responsiveness of target cells. Several types of mutations have been found in the AR and linked to endocrine dysfunctions. Surprisingly, the polymorphism involving the CAG triplet repeat expansion of the AR gene, coding for a polyglutamine (PolyGln) tract in the N-terminal transactivation domain of the AR protein, has been involved either in endocrine or neurological disorders. For example, among endocrine-related-diseases, the PolyGln size has been proposed to be associated to prostate cancer susceptibility, hirsutism, male infertility, cryptorchidism (in conjunction with polyglycine stretches polymorphism), etc.; the molecular mechanisms of these alterations are thought to involve a modulation of AR transcriptional competence, which inversely correlates with the PolyGln length. Among neurological alterations, a decreased AR function seems to be also involved in depression. Moreover, when the polymorphic PolyGln becomes longer than 35-40 contiguous glutamines (ARPolyGln), the ARPolyGln acquires neurotoxicity, because of an unknown gain-of-function. This mutation has been linked to a rare inherited X-linked motor neuronal disorder, the Spinal and Bulbar Muscular Atrophy, or Kennedy's disease. The disorder is characterized by death of motor neurons expressing high levels of AR. The degenerating motor neurons are mainly located in the anterior horns of the spinal cord and in the bulbar region; some neurons of the dorsal root ganglia may also be involved. Interestingly, the same type of PolyGln elongation has been found in other totally unrelated proteins responsible for different neurodegenerative diseases. A common feature of all these disorders is the formation of intracellular aggregates containing the mutated proteins; at present, but their role in the disease is largely debated. This review will discuss how the PolyGln neurotoxicity of SBMA AR may be either mediated or decreased by aggregates, and will present data on the dual role played by testosterone on motor neuronal functions and dysfunctions.