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The neuronotoxicity of genes with expanded CAG repeats is most likely mediated by their respective polyglutamine (Gln)-expanded gene products. Gln-expanded portions of these products may be sufficient, or necessary, for pathogenesis. We tested whether a Gln-expanded human androgen receptor (AR) is structurally altered, so that it allows for the proteolytic generation of a potentially pathogenic portion that may be resistant to further degradation. We found,  in vitro , that a Gln-expanded AR is more proteolytically resistant than normal, and that it yields a distinct set of Gln-expanded fragments even after extended proteolysis in the presence of 2 M urea. Furthermore, COS cells transfected with CAG-expanded AR cDNA generate an aberrant, nuclear-associated 75 kDa derivative containing the Gln-expanded tract. They are also twice as likely to die by 24 h apoptotically than those transfected with normal AR cDNA. Our data support the notion that an unconventional derivative of the Gln-expanded AR is a component of the proximate motor neuronopathic agent in spinobulbar muscular atrophy. They also focus attention on two ways in which neuro-notoxic derivatives may originate from various Gln-expanded proteins: (i) generation of an unusual derivative that is pathogenic  de novo ; and (ii) the toxic accumulation of a normal derivative because of an inability to dispose of it.

human molecular genetics

Spinobulbar Muscular Atrophy: Polyglutamine-expanded Androgen Receptor Is Proteolytically Resistant  in Vitro  and Processed Abnormally in Transfected Cells