Molecular Pathogenesis of the Polyglutamine Disease: Spinal and Bulbar Muscular Atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult onset neurodegenerative disease that affects men beginning in the fourth to fifth decade of life. The disease results from the expansion of a CAG trinucleotide repeat in the first exon of the androgen receptor gene. Symptoms of SBMA include weakness and atrophy of the proximal limb and bulbar muscles as well as partial androgen insensitivity. Cellular markers of disease include the loss of spinal motor neurons and the formation of nuclear aggregates of mutant androgen receptor protein (NII). The mechanism for pathogenesis in SBMA is unknown, and there is currently no treatment for the disease. New transgenic mouse, fly, and cell models of SBMA have provided important insights into the role of testosterone binding as a critical initiator of disease. An understanding of androgen receptor (AR) metabolism upon ligand binding is likely to provide new insights into the upstream events in SBMA pathogenesis. Moreover, the creation of novel models of disease is providing insights into abnormal neuronal responses to expanded AR accumulation. Here we discuss these ideas in the context of both basic AR biology and novel therapeutic development for SBMA. [ABSTRACT FROM AUTHOR]