Wild type huntingtin reduces the cellular toxicity of mutant huntingtin inmammalian cell models of Huntington's disease

Objectives-Recent data suggest that wild type huntingtin can protect agains t apoptosis in the testis of mice expressing full length huntingin transgen es with expanded CAG repeats. It is not clear if this protective effect was confined to particular cell types, or if wild type huntingtin exerted its protective effect in this model by simply reducing the formation of toxic p roteolytic fragments from mutant huntingtin. Methods-We cotransfected neuronal (SK-N-SH, human neuroblastoma) and non-ne uronal (COS-7, monkey kidney) cell lines with HD exon 1 (containing either 21 or 72 CAG repeats) construct DNA and either full length wild type huntin gtin or pFLAG (control vector). Results-Full length wild type huntingtin significantly reduced cell death r esulting from the mutant HD exon 1 fragments containing 72 CAG repeats in b oth cell lines. Wild type huntingtin did not significantly modulate cell de ath caused by transfection of HD exon 1 fragments containing 21 CAG repeats in either cell line. Conclusions-Our results suggest that wild type huntingtin can significantly reduce the cellular toxicity of mutant HD exon 1 fragments in both neurona l and non-neuronal cell Lines. This suggests that wild type huntingtin can be protective in different cell types and that it can act against the toxic ity caused by a mutant hunting in fragment as well as against a full length transgene.