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Accumulation of misfolded proteins is a common feature of several neurodegenerative disorders, including spinal and bulbar muscular atrophy (SBMA). SBMA is also known as Kennedy’s disease. SBMA belongs to the superfamily of polyglutamine diseases, which also includes Huntington’s disease, DRPLA, and six types of spinocerebellar ataxia. These disorders are caused by expansion of polyglutamine (polyQ) tracts in specific genes. SBMA is caused by polyQ expansion in the gene coding for androgen receptor (AR). In normal individuals, the polyQ tract of AR ranges from 9 to 36 residues, and expansion over 38 residues causes disease. SBMA is characterized by the loss of lower motor neurons, from brainstem and spinal cord, which is associated with progressive muscle weakness, fasciculation, and atrophy. Unique among polyQ diseases, SBMA is a sex-specific disease, with full disease manifestations occurring only in males. AR is the receptor for the male hormones, androgens. Androgen binding results in several post-translational modifications, which play a critical role in disease pathogenesis. In its inactive state, AR localizes to cytosol in association with heat shock proteins. Ligand binding leads to dissociation from heat shock proteins, dimerization, translocation to nucleus, and binding to specific DNA sequences, known as androgen-responsive elements (ARE). DNA binding is followed by recruitment of transcription co-factors, activators and repressors of transcription, and regulation of expression of androgen-responsive genes. The mechanism through which polyQ expansion in the AR causes motor neuron degeneration is not known. Others and we have previously shown that polyQ expansion in the AR alters several aspects of protein function. We showed that nuclear translocation is necessary, but not sufficient for pathogenesis. Moreover, we demonstrated that DNA binding is a prerequisite for toxicity, as polyQ-AR variants unable to bind DNA do not induce neurodegeneration in a fly model of disease. Binding of co-regulators of transcription is also critical for toxicity, as polyQ-AR variants that do not interact with transcription co-factors do not cause toxicity in flies. These data support the idea that native protein function is a critical component to disease pathogenesis.
In this application, we proposed to test the effect of different factors to disease pathogenesis, including protein context, protein-protein interaction, and cell context. This hypothesis is based on our preliminary data, which support the idea that the polyQ tract is not the sole determinant of disease pathogenesis. Based on the preliminary data described above, we are currently testing the central hypothesis that the toxicity of polyQ-AR is influenced at the post-translational level by phosphorylation of specific residues in the disease protein, by aberrant interaction with the Akt effector FOXO, and by tissue-specificity of disease protein expression. To test the hypothesis of this application, we are pursuing the following three specific aims:
Specific Aim 1: To characterize the impact of protein kinase A (PKA) on mutant AR toxicity.
Specific Aim 2: To characterize the role of FOXO in polyglutamine disease.
Specific Aim 3: Polyglutamine diseases: is the disease mechanism cell-autonomous?
With respect to Aim 1, we found that activation of PKA modifies the phosphorylation state of mutant AR. We obtained evidence that activation of PKA is protective in cultured cells. Indeed, activation of PKA reduces the cell death and toxicity caused by polyQ-AR. Importantly, activation of PKA reduced the accumulation of polyQ-AR in micro-oligomers, which are likely to represent toxic species.
To test the effect of protein-protein interaction in SBMA pathogenesis, we proposed to test the effect of FOXO activation in disease pathogenesis. We are investigating whether activation of FOXO is altered in the muscle of SBMA mice due to aberrant interaction with polyQ-AR. This hypothesis is based on our preliminary data, which show that activation of the insulin-like growth factor 1 (IGF-1)/Akt selectively in the muscle of SBMA mice reduces the toxicity of polyQ-AR. We previously showed that IGF-1 overexpression leads to Akt activation in skeletal muscle, and this in turn results in phosphorylation of polyQ-AR at serine 215 and serine 792. FOXO is a substrate of Akt, and phosphorylation of FOXO leads to its inactivation through nuclear exclusion of the protein. Because FOXO plays a major role in muscle atrophy, we proposed to test the hypothesis that aberrant interaction between FOXO and polyQ-AR results in overactivation of FOXO and muscle atrophy. We obtained evidence that phosphorylation of Akt, which is a measure of activation, is altered in the muscle of SBMA mice. This is consistent with the idea that FOXO is aberrantly activated in SBMA muscle.
To test the effect of cell-context in SBMA pathogenesis, we proposed to generate mice that express mutant AR in specific tissues. We generated mice for inducible expression of polyQ-AR in specific tissues.

Our results allowed us to identify important modifiers of polyQ-AR toxicity, i.e. PKA and FOXO. We propose such modifiers as novel therapeutic targets for SBMA.