Formation of polyglutamine inclusions in non-CNS tissue

Huntington's disease (HD) is one of a class of inherited progressive neurod egenerative disorders that are caused by a CAG/polyglutamine repeat expansi on, We have previously generated mice that are transgenic for exon 1 of the HD gene carrying highly expanded CAG repeats which develop a progressive m ovement disorder and weight loss with similarities to HD. Neuronal inclusio ns composed of the exon 1 protein and ubiquitin are present in specific bra in regions prior to onset of the phenotype, which in turn occurs long befor e specific neurodegeneration can be detected. In this report we have extend ed the search for polyglutamine inclusions to non-neuronal tissues, Outside the central nervous system (CNS), inclusions were identified in a variety of post-mitotic cells. This is consistent with a concentration-dependent nu cleation and aggregation model of inclusion formation and indicates that br ain-specific factors are not necessary for this process. To possibly gain i nsights into the wasting that is observed in the human disease, we have con ducted a detailed analysis of the timing and progression of inclusion forma tion in skeletal muscle and an investigation into the cause of the severe m uscle atrophy that occurs in the mouse model. The formation of inclusions i n non-CNS tissues will be particularly useful with respect to in vivo monit oring of pharmaceutical agents selected for their ability to prevent polygl utamine aggregation in vitro, without the requirement that the agent can cr oss the blood-brain barrier in the first instance.