For Researchers > Basic/Pre-Clinical Research > Movement Disorders > Pathogenesis and Neuronal Dysfunction in Polyglutamine Diseases

Pathogenesis and Neuronal Dysfunction in Polyglutamine Diseases

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) and Huntington's disease are part of growing family of neurodegenerative diseases caused by polyglutamine repeat expansion. The group also includes spinocerebellar ataxias types1, 2, 3, 6, 7, and 17, and Dentatorubropallidoluysian atrophy (DRPLA). With the exception of X-linked SBMA, all share an autosomal dominant mode of inheritance. Each of these diseases is associated with the loss of a specific subset of neurons despite widespread expression of the mutant protein. Studies of animal models, cell models, and patient tissue support the theory that these diseases are caused by a toxic property of the expanded polyglutamine. As with SBMA, a common pathological sign of abnormal metabolism is the presence of protein aggregation. Expanded polyglutamine proteins form neuronal aggregates containing all or part of the mutant protein.

The research in our lab is “disease-driven” basic research centered on understanding the molecular pathways by which motor neurons become dysfunctional in response to polyglutamine expansion in neurodegenerative disease. Many of the findings in our model system, spinal and bulbar muscular atrophy, are relevant to an array of polyglutamine diseases, as well as others that involve protein misfolding. These studies are designed to understand both the upstream pathogenic mechanisms of polyglutamine expansion diseases and the downstream effects on motor neuron dysfunction, with the ultimate goal of applying these understandings to therapeutic development.

The areas of investigation include:

1. Why do nuclear neuronal proteasomes fail to efficiently process expanded polyglutamine-containing proteins? How does the cellular stress response, or the lack thereof, factor into neuronal dysfunction in response to expanded polyglutamines? We are investigating nuclear-specific proteasome components, particularly PA28gamma, to determine their role in the resistance to proteasomal degradation of the mutant AR.
   
   
2. How is the degradation of the androgen receptor regulated? Unlike the other steroid hormone receptors, the AR is stabilized by hormone binding; what controls this stabilization, and how is its ultimate degradation regulated? What roles do nuclear import, nuclear export, DNA binding, and phosphorylation play in the regulation of AR catabolism? We are using inducible PC12 models to answer these questions.
   
   
3. What drives the motor neuron specificity of expanded-polyglutamine androgen receptor toxicity? Does the motor neuron expression of 5 alpha-reductase, which produces the most potent androgen, dihydrotestosterone, confer motor neuron susceptibility? We are testing this hypothesis using both pharmacologic and genetic approaches.
   
   
4. We have found reductions in the level of neurofilament heavy chain within motor neurons of diseased transgenic mice; this reduction is reversed by surgical castration. Does this molecular alteration result in alterations in axonal trafficking, leading to a loss of trophic support, and/or alterations at the neuromuscular junction? We are using transgenic mice and primary motor neuron cultures to determine the effect of polyglutamine expansion on axonal transport.
   
   
5. Markers of cellular senescence are induced in motor neurons of our diseased transgenic mice. Studies are underway to determine if the neuronal dysfunction in this disease is a result of premature initiation of a program of cellular senescence.