Genetically engineered mouse models of the trinucleotide-repeat spinocerebellar ataxias.

The spinocerebellar ataxias (SCAs) are dominantly inherited disorders that primarily affect coordination of motor function but also frequently involve other brain functions. The models described in this review address mechanisms of trinucleotide-repeat expansions, particularly those relating to polyglutamine expression in the mutant proteins. Modeling chronic late-onset human ataxias in mice is difficult because of their short life-span. While this potential hindrance has been partially overcome by using over-expression of the mutant gene, and/or worsening of the mutation by increasing the length of the trinucleotide repeat expansion, interpretation of results from such models and extrapolation to the human condition should be cautious. Nevertheless, genetically engineered murine models of these diseases have enhanced our understanding of the pathogenesis of many of these conditions. A common theme in many of the polyglutamine-repeat diseases is nuclear localization of mutant protein, with resultant effects on gene regulation. Conditional mutant models and transgenic knock-down therapy have demonstrated the potential for reversibility of disease when production of mutant protein is halted. Several other genetically engineered murine models of SCA also have begun to show utility in the identification and assessment of more classical drug-based therapeutic modalities.

Non-ATG-initiated translation directed by microsatellite expansions.

Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.