The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease

Intracellular inclusions are a unifying feature of polyglutamine (polyQ) ne urodegenerative diseases, yet each polyQ disease displays a unique pattern of neuronal degeneration. This implies that the protein context of expanded polyQ plays an important role in establishing selective neurotoxicity. Her e, in studies of the spinocerebellar ataxia type 3 disease protein ataxia-3 , we demonstrate that the protein sequence surrounding polyQ specifies the constituents of nuclear inclusions (NI) formed by the disease protein. The nuclear proteins cAMP response element-binding protein-binding protein (CBP ) and Mastermind-like-1 strongly colocalize only to NI formed by full-lengt h ataxia-3, whereas the splicing factor SC35 colocalizes only to NI formed by a polyQ-containing, carboxyl-terminal fragment of ataxia-3. These differ ences in NI formation reflect specific protein interactions normally undert aken by ataxia-3, as both normal and mutant full-length ataxia-3 co-immunop recipitate with CBP and sediment on density gradients as macromolecular com plexes. Moreover, normal ataxia-3 represses cAMP response element-binding p rotein-mediated transcription, indicating a functional consequence of ataxi a-3 interactions with CBP. Finally, we show that mutant ataxia-3 forms inso luble intranuclear complexes, or MIL croaggregates, before NI can be detect ed, implying a precursor-product relationship. These results suggest that p rotein context-dependent recruitment of nuclear proteins to intranuclear mi croaggregates, and subsequently to NI, may contribute to selective neurotox icity in polyQ diseases.