Sci. Aging Knowl. Environ., 1 October 2003
Vol. 2003, Issue 39, p. nw134
[DOI: 10.1126/sageke.2003.39.nw134]

NOTEWORTHY ARTICLES

Messmaker

Enzyme creates garbage backup that's linked to Alzheimer's disease

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/39/nw134

Key Words: ubiquitin ligase • ubiquitin-conjugating enzyme

Obstructions in the cellular trash compactor might accelerate neuron destruction in Alzheimer's disease (AD), and a new study identifies an enzyme that promotes these dangerous clogs. The work fills in a missing piece of how the AD-associated {beta}-amyloid protein snarls the cellular waste-management system and identifies a possible target for anti-AD drugs.

Cells possess machinery for destroying used or damaged proteins, and glitches in that equipment might speed the neuronal die-off characteristic of AD and perhaps foster aging (see Gray Review). The hallmark brain plaques of AD contain the protein ubiquitin, a molecule that marks other proteins for destruction; the accumulation suggests that the cell's garbage-disposal system can't efficiently clear damaged proteins. In addition, an abnormal variant of ubiquitin--called UBB+1--frequently builds up in the brains of Alzheimer's patients. Cell culture experiments revealed that this alternate form jams a machine called the proteasome, which vaporizes ubiquitin-tagged proteins. Normally, cells build chains of ubiquitin molecules on proteins that are ready for disposal. But cells can construct ubiquitin chains on UBB+1 that aren't hooked to such proteins; the resulting trees gum up the proteasome. Researchers hadn't yet identified the enzyme that forges these futile chains.

While searching for new proteins involved in AD, Song and colleagues stumbled onto an enzyme that might fit the bill. The researchers bathed rat neurons with {beta} amyloid, a protein that forms clumps that likely cause AD-related neurodegeneration. The amyloid treatment activated 17 genes that remain silent in untreated cells. One of those genes encodes an enzyme--called E2-25K/Hip-2--known to build ubiquitin chains. What's more, brains from human AD patients and from mice that carry AD-causing mutations harbored unusually large amounts of E2-25K/Hip-2, and the protein appeared in the same brain regions as UBB+1 did. The observations hinted that excess E2-25K/Hip-2 might spur neuron death in response to {beta} amyloid.

To explore that idea, the team analyzed E2-25K/Hip-2 function in neurons. After treatment with {beta} amyloid, cells that lacked the enzyme--or that carried a crippled version--survived longer than did cells with functioning E2-25K/Hip-2. And neurons that made extra E2-25K/Hip-2 were more vulnerable to {beta}-amyloid poisoning. Additional experiments revealed that adding {beta} amyloid squelches proteasome activity and that hindering E2-25K/Hip-2 function prevents the blockage. Moreover, E2-25K/Hip-2 encourages the formation of faulty ubiquitin chains in {beta}-amyloid-treated cells; cells without operational E2-25K/Hip-2 lack the chains. Together, the results suggest that in response to {beta} amyloid, E2-25K/Hip-2 forges ubiquitin chains that block the proteasome, thereby encouraging cell death.

By connecting {beta} amyloid to proteasome inhibition, E2-25K/Hip-2 is "like the piece of the jigsaw that links two edges of the puzzle," says neuroscientist Andrew Hope of University College London. If further studies confirm the results, E2-25K/Hip-2 "would be a good target for therapy," he says. Future work should aim to uncover how E2-25K/Hip-2 stifles protein degradation, such as whether it decorates UBB+1 or other molecules, says molecular biologist Cecile Pickart of Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Such studies might reveal why cells in Alzheimer's patients fail to take out the trash.

--R. John Davenport


October 1, 2003
  1. S. Song et al., Essential role of E2-25K/Hip-2 in mediating amyloid-{beta} neurotoxicity. Mol. Cell 12, 553-563 (2003). [Abstract] [Full Text] [CrossRef][Medline]
Citation: R. J. Davenport, Messmaker. Sci. SAGE KE 2003 (39), nw134 (2003).








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