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Spinal and bulbar muscular atrophy (SBMA) is an adult onset, X-linked neuromuscular disease. The causative mutation was identified in 1991 by Dr. Fischbeck's group to be expansions of the CAG triplet repeats (>38 CAGs) in exon 1 of the androgen receptor (AR) gene. Clinically, SBMA is characterized by cramps, bulbar fasciculations, dysphagia, bulbar and proximal muscle atrophy, testicular atrophy, and gynecomastia. AR belongs to the family of steroid receptors that translocates into the nucleus upon androgen binding and functions as a transcription factor. There is mounting evidence for a role for mutant AR-mediated transcriptional dysregulation and ligand-dependent toxicity in SBMA.

Mitochondrial dysfunction has been implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and Huntington's disease (HD). However, it is not known whether mutant AR affects mitochondria in SBMA. It is likely that aberrant nuclear events could lead to mitochondrial dysregulation. Recent findings in HD, another polyQ disease, suggest a nuclear factor called peroxisome activated receptor ?-coactivator-1 (PGC-1) to be a link between transcriptional dysregulation and mitochondrial dysfunction. Alterations in mitochondrial function can result in a cascade leading to apoptotic cell death, and is a possible explanation for the motor neuron cell death, which is a pathological hallmark of SBMA. Preliminary data from our group suggests that mutant AR affects mitochondrial function and that it results in caspase activation. Another downstream effect of mitochondrial dysfunction is an elevation of reactive oxygen species (ROS) and alterations in the levels of antioxidant.

The hypothesis in this study is to examine whether mutant AR-mediated mitochondrial dysfunction in SBMA is linked to oxidative stress. We used motor neuron-like cell lines (MN1) and knock-in mouse models to assess levels of ROS and antioxidants. We did fluorometric assays, Westerns, immunocytochemistry, real-time polymerase chain reaction (RT-PCR), and fluorescence-activated cell sorting (FACS). We show that in MN1 cells, mutant AR increases levels of ROS, which can be blocked with mitochondrial modulators and antioxidants. Preliminary results from Westerns and immunocytochemistry suggest alterations in antioxidant levels. In addition, pilot studies in MN1 cells suggest that mitochondrial levels and morphology may be altered in cells containing mutant AR. In summary, these results suggest an involvement of mitochondria and oxidative stress in SBMA with antioxidants as plausible therapeutic options.

Last updated November 16, 2007