Toward an understanding of polyglutamine neurodegeneration

Polyglutamine expansion is now recognized to be a major cause of inherited human neurodegenerative disease. The polyglutamine expansion diseases ident ified so far are slowly progressive disorders in which distinct yet overlap ping brain regions are selectively vulnerable to degeneration. Despite thei r clinical differences these diseases likely share a common pathogenic mech anism, occurring at the protein level and centered on an abnormal conformat ion of expanded polyglutamine in the respective disease proteins. Recently there has been remarkable progress in our understanding of polyglutamine di sease, but still there are many unanswered questions. In this review, I fir st outline some of the shared features of polyglutamine diseases and then d iscuss several issues relevant to an understanding of pathogenesis, paying particular attention to possible mechanisms of neurotoxicity.