Expanded polyglutamine domain proteins bind neurofilament and alter the neurofilament network

Eight inherited neurodegenerative diseases are caused by genes with expande d CAG; repeats coding for polyglutamine domains in the disease-producing pr oteins. The mechanism by which this expanded polyglutamine domain causes ne urodegenerative disease is unknown, but nuclear and cytoplasmic polyglutami ne protein aggregation is a common feature. In transfected COS7 cells, expa nded polyglutamine proteins aggregate and disrupt the vimentin intermediate filament network. Since neurons have an intermediate filament network comp osed of neurofilament (NF) and NF abnormalities occur in neurodegenerative diseases, we examined whether pathologic-length polyglutamine domain protei ns also interact with NF. We expressed varying lengths polyglutamine-green fluorescent protein fusion proteins in a neuroblast cell line, TR1. Patholo gic-length polyglutamine-GFP fusion proteins formed large cytoplasmic aggre gates surrounded by neurofilament. Immunoisolation of pathologic-length pol yglutamine proteins coisolated 68-kDa NF protein demonstrating molecular in teraction. These observations suggest that polyglutamine interaction with N F is important in the pathogenesis of the polyglutamine repeat diseases. (C ) 1999 Academic Press.