Double-stranded RNA-dependent protein kinase, PKR, binds preferentially toHuntington's disease (HD) transcripts and is activated in HD tissue

Fourteen neurological diseases have been associated with the expansion of t rinucleotide repeat regions. These diseases have been categorized into thos e that give rise to the translation of toxic polyglutamine proteins and tho se that are untranslated. Thus far, compelling evidence has not surfaced fo r the inclusion of a model in which a common mechanism may participate in t he pathobiology of both translated and untranslated trinucleotide diseases. In these studies we show that a double-stranded RNA-binding protein, PKR, which has previously been linked to virally-induced and stress-mediated apo ptosis, preferentially binds mutant huntingtin RNA transcripts immobilized on streptavidin columns that have been incubated with human brain extracts. These studies also show, by immunodetection in tissue slices, that PKR is present in its activated form in both human Huntington autopsy material and brain tissue derived from Huntington yeast artificial chromosome transgeni c mice. The increased immunolocalization of the activated kinase is more pr onounced in areas most affected by the disease and, coupled with the RNA bi nding results, suggests a role for PKR activation in the disease process.