Mitigation of the SBMA phenotype

Cell culture and animal model experiments have produced useful information as to how best to mitigate the SBMA phenotype. As molecular chaperones recognize and renature misfolded proteins (aggregate), it was thought that they might reverse the polyQ toxicity. In cell culture experiments, overexpression of molecular chaperones reduced aggregate formation and suppressed apoptosis in neuronal cell models of SBMA (Bailey etal. 2002; Ishihara etal. 2003; Kobayashi etal. 2000). Overexpression of molecular chaperones has also been shown to restore the disrupted eye phenotype obtained in the Drosophila SBMA model (Chan etal. 2002; Takeyama etal. 2002). The molecular chaperones that possess this salvaging function are diverse. They range from hsp70 to hsp40 and hsp105a (Bailey et al. 2002; Chan et al. 2002; Ishihara etal. 2003; Kobayashi etal. 2000; Takeyama etal. 2002).

One established property of glutamine residues is their ability to act as amine acceptors in transglutaminase-catalysed reactions resulting in proteolytic resistant glutamyl-lysine cross links. Thus the N-terminal fragment of the AR may function as substrate for transglutaminases (Mandrusiak et al. 2003). Transglutaminase-mediated isopeptide bonds have been detected in brains of SBMA transgenic mice but not in controls, suggesting the involvement of transglutaminase-catalysed reactions in polyQ disease pathology. Consistent with this, the transglutaminase inhibitor, cystamine, has been shown to prevent aggregates caused by expanded polyQ stretch in the AR or ligand-dependent proteasome dysfunction associated with polyQ amplification (Becker etal. 2000; Mandrusiak etal. 2003).

Cell death induced by the polyQ amplification can also be mitigated by overexpression of full-length cAMP response element binding protein (CREB)-binding protein (CBP). CBP is one of the several histone acetyltransferases sequestered by polyQ inclusions (McCampbell et al. 2000). Thus histone acetylation is reduced in cells expressing amplified polyQ stretches. Reversal of this hypoacetylation by overexpression of CBP or treatment with histone deacetylase inhibitors reduce the cell loss (McCampbell etal. 2001).

2.8 Key messages

• The AR has a modular structure composed of three main domains: the NH2-terminal domain necessary for transactivation, the centrally located DNA binding domain and the COOH-terminal domain required for hormone binding.

• The hormone binding domain exists in a complex with molecular chaperones and co-chaperones that are necessary for providing the receptor with the correct conformation for hormone binding. The molecular chaperones and co-chaperones also play a more active role in transactivation by the receptor by possibly providing the appropriate conformation for coactivators to bind to the receptor.

• The AR exerts a novel action that leads to the activation of several signal transduction cascades. This response is rapid, non-transcriptional and occurs within seconds to minutes, mimicking the action of growth factor receptors.

• In addition to androgens, the AR can also be activated in a ligand-independent manner by MAP kinases, cAMP and IL-6. These factors activate diverse signaling pathways and they all seem to trigger the function of the AR via site-specific phosphorylation events.

• Growth and maintenance of function of the prostate are critically dependent on AR function. Androgen withdrawal or AR inhibition results in induction of apoptosis in prostate epithelial cells and this forms the basis for endocrine therapy of prostate cancer.

• Prostate tumors escape from androgen ablation therapy by developing a hyperreative AR that is activated under the condition of androgen deprivation by means of mutations that generate promiscuous receptors, increased AR expression, enhanced ligand-independent activation or dysregulation of AR activity modulating proteins.

• Spinal and bulbar muscular atrophy (SBMA; Kennedy syndrome) is caused by a pathological amplification of the CAG repeat number and it is associated with the formation of cytoplasmic and/or nuclear aggregates. This disorder is ligand-dependent and requires transport of the mutated receptor into the nucleus.

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