Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity

Mol Cell. 2003 Sep;12(3):553-63. doi: 10.1016/j.molcel.2003.08.005.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Apoptosis / genetics
  • Brain / enzymology*
  • Brain / pathology
  • Brain / physiopathology
  • Cells, Cultured
  • Cysteine Endopeptidases / metabolism
  • Female
  • Fetus
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Ligases / genetics
  • Ligases / metabolism*
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism
  • Multienzyme Complexes / metabolism
  • Mutation / genetics
  • Neurons / enzymology*
  • Neurons / pathology
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity
  • Proteasome Endopeptidase Complex
  • Rats
  • Ubiquitin / genetics
  • Ubiquitin / metabolism
  • Ubiquitin-Conjugating Enzymes*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*

Substances

  • Amyloid beta-Peptides
  • Multienzyme Complexes
  • Peptide Fragments
  • Ubiquitin
  • amyloid beta-protein (1-42)
  • UBE2K protein, human
  • Ubiquitin-Conjugating Enzymes
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP3K5 protein, human
  • Map3k5 protein, mouse
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Ligases