Abstract
Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, which are also ubiquitinated, indicating impairment of the ubiquitin-proteasome system. E2-25K (Hip2), an ubiquitin-conjugating enzyme, interacts directly with huntingtin and may mediate ubiquitination of the neuronal intranuclear inclusions in Huntington disease. E2-25K could thus modulate aggregation and toxicity of expanded huntingtin. Here we show that E2-25K is involved in aggregate formation of expanded polyglutamine proteins and polyglutamine-induced cell death. Both a truncated mutant, lacking the catalytic tail domain, as well as a full antisense sequence, reduce aggregate formation. Strikingly, both E2-25K mutants also reduced polyglutamine-induced cell death. In postmortem brain material of both Huntington disease and SCA3, E2-25K staining of polyglutamine aggregates was observed in a subset of neurons bearing intranuclear neuronal inclusions. These results demonstrate that targeting by ubiquitination plays an important role in the pathology of polyglutamine diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Brain / enzymology*
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Brain / pathology
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Brain / physiopathology
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Catalytic Domain / genetics
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Cell Death / genetics
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Cell Line, Tumor
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Humans
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Huntingtin Protein
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Huntington Disease / enzymology
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Huntington Disease / genetics
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Huntington Disease / physiopathology
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Intranuclear Inclusion Bodies / enzymology*
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Intranuclear Inclusion Bodies / genetics
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Intranuclear Inclusion Bodies / pathology
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Machado-Joseph Disease / enzymology
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Machado-Joseph Disease / genetics
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Machado-Joseph Disease / physiopathology
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Mutation / genetics
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Nerve Degeneration / enzymology*
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Nerve Degeneration / genetics
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Nerve Degeneration / physiopathology
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Nerve Tissue Proteins / metabolism
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Neurons / enzymology*
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Neurons / pathology
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Nuclear Proteins / metabolism
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Peptides / genetics
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Peptides / metabolism*
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Ubiquitin-Conjugating Enzymes / chemistry
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Ubiquitin-Conjugating Enzymes / genetics
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Ubiquitin-Conjugating Enzymes / metabolism*
Substances
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HTT protein, human
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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polyglutamine
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UBE2K protein, human
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Ubiquitin-Conjugating Enzymes