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The research in my lab centers on understanding the molecular pathways by which motor neurons become dysfunctional in response to expression of polyglutamine-expanded androgen receptor in the neurodegenerative disease spinal and bulbar muscular atrophy. These studies are generally designed to understand how neurons respond to the accumulation of misfolded proteins.
Spinal and bulbar muscular atrophy (SBMA): a motor neuron disease caused by trinucleotide repeat expansion. The expansion of a polyglutamine-encoding CAG trinucleotide repeat within the androgen receptor (AR) gene causes the motor neuron degenerative disease spinal and bulbar muscular atrophy. We have shown that androgen binding by the mutant polyglutamine-expanded AR is required for disease. Our focus now lies in understanding the steps downstream of hormone binding that impact toxicity.
The areas of investigation are based on the following questions:
At what point in androgen receptor trafficking and metabolism do things go wrong? The mutant AR, while normal in its transcriptional function, fails to be properly degraded. At what point in its life-cycle does its metabolism go awry? What roles do nuclear import, nuclear export, DNA binding, and post-translational modifications play in the regulation of AR catabolism? What role does proteolytic cleavage play in disease?
Why do nuclear neuronal proteasomes fail to efficiently process expanded polyglutamine-containing proteins? We have found that manipulation of the nuclear isoform of the 11S proteasomal regulator PA28 substantially modulates AR aggregation. Ongoing studies evaluate whether PA28gamma is required for disease and whether it is involved in the normal degradation of AR.
Where do we turn for therapies? Understanding the molecular details of mutant AR metabolism should lead us to novel therapeutic approaches. We have identified several compounds that promote the turnover of expanded AR; these are currently under evaluation for therapeutic development.
Approaches: We utilize biochemical, molecular and cell biological approaches to address the questions under investigation. Our systems primarily include transgenic mice, cultured cell models, and primary motor neuron cultures.
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