Trinucleotide repeat disease. The androgen receptor in spinal and bulbar muscular atrophy.

摘要

It has been more than 10 years since the discovery that the expansion of a simple CAG trinucleotide repeat within the coding region of the androgen receptor gene leads to the motor neuronopathy spinal and bulbar muscular atrophy (SBMA). A flurry of investigation into this and the other, more recently discovered, polyglutamine diseases has led to an understanding of many aspects of the molecular pathogenesis of this family of diseases. A characteristics pathological feature of the polyglutamine diseases is the occurrence in affected neurons of ubiquitinated aggregates; such aggregates also contain, among others, proteins involved in the folding and degradation of the mutant proteins. Aggregates themselves are likely not directly cytotoxic, but rather mark the accumulation of all or part of the mutant protein. Furthermore, aggregation occurs because of the inefficient clearance of the mutant protein by the ubiquitin-proteasome pathway for protein degradation. These findings are common to the polyglutamine diseases and reflect the general problem of folding/degrading expanded polyglutamines. In SBMA, the altered metabolism of the androgen receptor is ligand dependent. How the accumulation of the mutant protein causes neuronal dysfunction and disease is not well understood, but several cellular processes have been implicated. Although these findings provide insight into the toxic function of the expanded polyglutamine protein, additional investigations have led to the finding that intrinsic AR transactivational function is somewhat diminished in the presence of the expanded polyglutamine; this likely leads to the partial androgen insensitivity that characterizes patients with SBMA. The recent development of useful animal and cell models of SBMA will lead to increased understanding of disease pathogenesis, as well as to the development of new and better therapeutic strategies.