Abstract
The ubiquitin/proteasome system has been proposed to play an important role in Alzheimer's disease (AD) pathogenesis. However, the critical factor(s) modulating both amyloid-beta peptide (Abeta) neurotoxicity and ubiquitin/proteasome system in AD are not known. We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity. The expression of E2-25K/Hip-2 was upregulated in the neurons exposed to Abeta(1-42) in vivo and in culture. Enzymatic activity of E2-25K/Hip-2 was required for both Abeta(1-42) neurotoxicity and inhibition of proteasome activity. E2-25K/Hip-2 functioned upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta(1-42) toxicity. Further, the ubiquitin mutant, UBB+1, a potent inhibitor of the proteasome which is found in Alzheimer's brains, was colocalized and functionally interacted with E2-25K/Hip-2 in mediating neurotoxicity. These results suggest that E2-25K/Hip-2 is a crucial factor in regulating Abeta neurotoxicity and could play a role in the pathogenesis of Alzheimer's disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / enzymology*
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Alzheimer Disease / genetics
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / toxicity
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Animals
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Apoptosis / genetics
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Brain / enzymology*
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Brain / pathology
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Brain / physiopathology
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Cells, Cultured
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Cysteine Endopeptidases / metabolism
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Female
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Fetus
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Gene Expression Regulation, Enzymologic / physiology
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Humans
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JNK Mitogen-Activated Protein Kinases
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Ligases / genetics
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Ligases / metabolism*
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinases / metabolism
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Multienzyme Complexes / metabolism
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Mutation / genetics
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Neurons / enzymology*
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Neurons / pathology
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Peptide Fragments / metabolism
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Peptide Fragments / toxicity
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Proteasome Endopeptidase Complex
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Rats
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Ubiquitin / genetics
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Ubiquitin / metabolism
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Ubiquitin-Conjugating Enzymes*
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Up-Regulation / drug effects
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Up-Regulation / physiology*
Substances
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Amyloid beta-Peptides
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Multienzyme Complexes
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Peptide Fragments
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Ubiquitin
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amyloid beta-protein (1-42)
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UBE2K protein, human
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Ubiquitin-Conjugating Enzymes
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases
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MAP3K5 protein, human
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Map3k5 protein, mouse
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Ligases