The Role of Protein Composition in Specifying Nuclear Inclusion Formation in Polyglutamine Disease

摘要: Intracellular inclusions are a unifying feature of polyglutamine (polyQ) neurodegenerative diseases, yet each polyQ disease displays unique pattern neuronal degeneration. This implies that the protein context expanded plays an important role in establishing selective neurotoxicity. Here, studies spinocerebellar ataxia type 3 ataxin-3, we demonstrate sequence surrounding specifies constituents nuclear (NI) formed by protein. The proteins cAMP response element-binding protein-binding (CBP) and Mastermind-like-1 strongly colocalize only to NI full-length whereas splicing factor SC35 colocalizes polyQ-containing, carboxyl-terminal fragment ataxin-3. These differences formation reflect specific interactions normally undertaken as both normal mutant ataxin-3 co-immunoprecipitate with CBP sediment on density gradients macromolecular complexes. Moreover, represses protein-mediated transcription, indicating functional consequence CBP. Finally, show forms insoluble intranuclear complexes, or microaggregates, before can be detected, implying precursor-product relationship. results suggest context-dependent recruitment subsequently NI, may contribute neurotoxicity diseases.