Spinal And Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), an X-linked disorder, usually manifests with slowly progressive proximal weakness in the third through fifth decades. The disease, mapped to Xq11-q12, is caused by expanded CAG repeats encoding a polyglutamine tract in the androgen receptor protein. Disease-linked alleles (37-66 CAGs) change length when transmitted from parents to children, with an increased tendency to change when inherited through the father. Individuals with longer CAG repeats have early onset disease. Neuropatholo-gically, there is degeneration of lower motor neurons in spinal cord and brain stem, accompanied by local gliosis and atrophy of skeletal muscles. Both the wildtype and the mutant androgen receptor are widely distributed, predominantly in the cytoplasm of neurons. Nuclear ubiquitin-immunoreactive inclusions containing the mutant androgen receptor are observed in spinal motor neurons of SBMA but not in other, unaffected neural tissues. Similar nuclear inclusions are seen in some nonneural tissues. The mechanism whereby the expanded trinucleotide repeats cause disease, including Huntington's disease, is the subject of exciting recent research. Although there is an indication that the expanded repeat causes some loss of transcriptional activity by the androgen receptor, the major influence of the expansion is likely related to a gain of toxic function.

Recent advances in neuronal cell culture and transgenic models have documented pathological findings that resemble those observed in individuals with Kennedy's disease. Cell culture studies have indicated that the aggregation and proteolytic processing of the androgen receptor are dependent on the length of the polyglutamine repeat. Moreover, the abnormal metabolism of the expanded repeat androgen receptor is associated with cellular toxicity. These results suggest a molecular basis for the neurotoxic gain of function associated with neuronal degeneration in SBMA. Initial transgenic mice expressing the human androgen receptor cDNAs with 45 or 66 CAG repeats driven by a variety of promoters failed to reveal any pathological phenotype. Recently, mice expressing a truncated androgen receptor with 112 CAG repeats driven by the prion protein promoter showed a remarkable neurological abnormality associated with tremor, gait problem, circling behavior, and seizures. As observed in SBMA cases, nuclear inclusions are found in motor neurons of these transgenic mice. Several lines of yeast artificial chromosome (YAC) transgenic mice carrying 45 CAG repeat expansions in the androgen receptor showed an ~ 10% rate of repeat length instability. In addition, the 45 CAG repeat tracts caused greater instability with maternal transmission and with older transmitting female. These studies indicate that human locus-specific sequences are necessary to generate trinucleotide repeat instability in mice. Further efforts to identify the czs-acting elements that permit CAG tract instability and the trans-acting factors that regulate repeat instability will be useful to clarify the molecular basis of trinucleotide repeat instability in SBMA.

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