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

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.

• Authors: Sungmin Song, So-Young Kim, Yeon-Mi Hong, Dong-Gyu Jo, Joo-Yong Lee, Sang Mi Shim, Chul-Woong Chung, Soo Jung Seo, Yung Joon Yoo, Jae-Young Koh, Min Chul Lee, Allan J Yates, Hidenori Ichijo, Yong-Keun Jung
• Journal: Molecular cell (Mol Cell) Vol. 12 Issue 3 Pg. 553-63 (Sep 2003) ISSN: 1097-2765 [Print] United States
• PMID: 14527403 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (enzymology, genetics)
• Amyloid beta-Peptides (metabolism, toxicity)
• Animals
• Apoptosis (genetics)
• Brain (enzymology, pathology, physiopathology)
• Cells, Cultured
• Cysteine Endopeptidases (metabolism)
• Female
• Fetus
• Gene Expression Regulation, Enzymologic (physiology)
• Humans
• JNK Mitogen-Activated Protein Kinases
• Ligases (genetics, 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, pathology)
• Peptide Fragments (metabolism, toxicity)
• Proteasome Endopeptidase Complex
• Rats
• Ubiquitin (genetics, metabolism)
• Ubiquitin-Conjugating Enzymes
• Up-Regulation (drug effects, physiology)