Pathogenesis of Polyglutamine-Induced Disease: A Model for SCA1

Abstract During the past 7 years several inheritable neurological disorders have been found to be due to the expansion of an unstable CAG trinucleotide repeat that leads to an increase in the length of a polyglutamine tract within a disease-specific protein. Based on pathological evidence obtained from the brains of affected individuals and transgenic mice expressing a mutant human gene, it was proposed that the formation of nuclear aggregates of the polyglutamine protein plays a critical role in pathogenesis. However, recent evidence indicates that this may not be the case. This review focuses on our results for one of these disorders, spinocerebellar ataxia type 1 (SCA1), and presents a model for SCA1 pathogenesis.