Intracellular inclusions are a unifying feature of polyglutamine (polyQ) neurodegenerative 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. Here, in studies of the spinocerebellar ataxia type 3 disease protein ataxin-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-length ataxin-3, whereas the splicing factor SC35 colocalizes only to NI formed by a polyQcontaining, carboxyl-terminal fragment of ataxin-3. Thes
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