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

Yaohui Chai, Lizi Wu, James D. Griffin, Henry L. Paulson

Research output: Contribution to journalArticle

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Abstract

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 polyQ-containing, carboxyl-terminal fragment of ataxin-3. These differences in NI formation reflect specific protein interactions normally undertaken by ataxin-3, as both normal and mutant full-length ataxin-3 co-immunoprecipitate with CBP and sediment on density gradients as macromolecular complexes. Moreover, normal ataxin-3 represses cAMP response element-binding protein-mediated transcription, indicating a functional consequence of ataxin-3 interactions with CBP. Finally, we show that mutant ataxin-3 forms insoluble intranuclear complexes, or microaggregates, before NI can be detected, implying a precursor-product relationship. These results suggest that protein context-dependent recruitment of nuclear proteins to intranuclear microaggregates, and subsequently to NI, may contribute to selective neurotoxicity in polyQ diseases.

Original languageEnglish (US)
Pages (from-to)44889-44897
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number48
DOIs
StatePublished - Nov 30 2001

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Intranuclear Inclusion Bodies
Chemical analysis
Proteins
Cyclic AMP Response Element-Binding Protein
Nuclear Proteins
Neurodegenerative diseases
Macromolecular Substances
Machado-Joseph Disease
Ataxin-3
polyglutamine
Transcription
Cytomegalovirus Infections
Protein Binding
Neurodegenerative Diseases
Carrier Proteins
Sediments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The Role of Protein Composition in Specifying Nuclear Inclusion Formation in Polyglutamine Disease. / Chai, Yaohui; Wu, Lizi; Griffin, James D.; Paulson, Henry L.

In: Journal of Biological Chemistry, Vol. 276, No. 48, 30.11.2001, p. 44889-44897.

Research output: Contribution to journalArticle

Chai, Yaohui ; Wu, Lizi ; Griffin, James D. ; Paulson, Henry L. / The Role of Protein Composition in Specifying Nuclear Inclusion Formation in Polyglutamine Disease. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 48. pp. 44889-44897.
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