For Researchers > Basic/Pre-Clinical Research > Movement Disorders > Spinal and Bulbar Muscular Atrophy (SBMA)

Spinal and Bulbar Muscular Atrophy (SBMA)

X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a slowly progressive neuromuscular disorder characterized by the loss of motor neurons in the spinal cord and brainstem. The main pathological finding in SBMA is motor neuron loss in the anterior horn cells of the spinal cord and in motor nuclei in the brainstem, with a subclinical loss of sensory neurons in the dorsal root ganglia. Another pathological marker of the disease is the presence of AR-containing ubiquitinated neuronal intranuclear inclusions (NII) in motor neurons of the anterior horn of the spinal cord, and at a lower frequency in regions unaffected in SBMA (e.g., dermis, scrotal skin, testis, heart, and kidney).

SBMA is caused by the expansion of a polymorphic trinucleotide CAG repeat within the androgen receptor ( AR ) gene . This expansion within exon 1 of the AR gene leads to expression of an expanded polyglutamine repeat within the AR protein. The polyglutamine tract contains 40-62 residues in SBMA patients, but only 10-36 residues in normal individuals. The age of onset is inversely correlated with repeat length, such that the longer the repeat region, the earlier the age of onset. Our goals are to understand how expanded polyglutamine tracts become toxic to neurons, using SBMA as a model, and to translate those understandings into therapies for SBMA as well as other polyglutamine diseases.

Toward that end, w e have developed a transgenic model of SBMA using mice bearing a human AR with 112 glutamines (AR112Q). This model reproduces many aspects of SBMA, including slowly progressive, gender-specific motor deficits and neuronal intranuclear inclusions. Despite substantial motor deficits in male AR112Q mice, no motor neuron loss was observed, indicating that neuronal dysfunction , rather than neuronal death , is central to disease. Moreover, reduced levels of unphosphorylated neurofilament heavy chain (NF-H) were observed in motor neurons, suggesting a role for NF-H in SBMA neuronal dysfunction. The elimination of androgens by surgical castration of severely affected, aged 112Q male mice partially restored motor function as well as NF-H levels. These data suggest that hormone-based therapies designed to treat SBMA patients, even with advanced disease, are likely to be effective.

We are now using the mouse model in basic research aimed at understanding the fundamental mechanisms of polyglutamine disease pathogenesis and neuronal dysfunction , and in preclinical efficacy studies testing compounds that we and others have identified that show promise for therapeutic benefit based on preliminary cellular assays.