How does expansion of the polyglutamine tract in the androgen receptor cause motor neuron dysfunction and cell death?

The research in my lab centers on two areas of investigation to understand the molecular pathogenesis of the neurodegenerative disease spinal and bulbar muscular atrophy, which is caused by polyglutamine expansion within the androgen receptor (AR). 1) To understand the molecular basis for DHT-dependent AR misfolding, aggregation and toxicity; and 2) To develop an understanding of the molecular pathways by which motor neurons become dysfunctional in response to expression of the mutant protein. 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. Moreover, we have found that nuclear localization of the mutant AR is necessary, but not sufficient, to cause 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 DNA binding, nuclear export and post-translational modifications play in AR aggregation and toxicity? What role does proteolytic cleavage play in disease? We have recently found that an interdomain interaction of the AR, the N/C interaction, plays a role in mutant AR aggregation and toxicity. Ongoing studies are evaluating the mechanism(s) underlying this finding.

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 (PA28³) substantially modulates AR aggregation. Moreover, PA28³ protects motor neurons from mutant AR toxicity. Ongoing studies are evaluating the mechanism by which PA28³ is neuroprotective.

WHERE DO WE TURN FOR THERAPIES? Understanding the molecular details of mutant AR metabolism should lead us to novel therapeutic approaches. Based on our finding that the N/C interaction plays a role in AR aggregation and toxicity, we have identified several AR ligands that prevent the N/C interaction and promote motor neuron viability. Preclinical studies of these compounds in a transgenic mouse model of SBMA are ongoing.

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.