CHEMICAL & ENGINEERING
NEWS OF THE WEEK iuGUST L
2006 - EDITED BY VsilULIAM 6. S(Uuilz & MELISSA KUHNELL.
BIOCHEMISTRY
TWO-PATH MECHANISM Protective pathways may falter with age, sparking Alzheimer's neurodegeneration
A
COLLABORATIVE TEAM HAS
shown that cell damage from protein aggregation in Alzheimer's disease can be greatly reduced by experimentally slowing the appearance of signs of aging and has revealed a dual-pathway mechanism by which this effect may occur. Other groups had shown before thatretardingthe hallmarks of aging protects against neuronal toxicity associated with a related condition, Huntington's disease, but they didn't demonstrate the mechanism. The new study identifies two previously unknown neuroprotective pathways that may work increasingly less well as organisms age, helping to explain the close association between aging and Alzheimer's at a molecular level. One pathway disassembles protein aggregates so they can't harm cells. The second, which likely is activated when the first is overtaxed, protects cells by converting small toxic aggregates into less toxic larger ones, perhaps so they can be stored until they can be disposed of properly. The pathways should reveal molecular targets to which future Alzheimer's medications can be directed. The study was carried out by professor of molecular and cell biology Andrew Dillin of Salk InstituteforBiological Studies, LaJolla, Calif.; chemistry professorJeffery W. Kelly of Scripps Research Institute; and coworkers (Science, DOI: 10.1126/science.ll24646). In a WWW.CEN-0NLINE.ORG
worm model of Alzheimer's, they identified the two pathways by using RNA interference to manipulate the expression of transcription factors that control lifespan and by using kinetic assays to monitor protein aggregation. The preferred pathway breaks down Alzheimer's |}-peptide (A(i) oligomers or small aggregates. "The need for this pathway to be turned on is continual," says D. Stephen Snyder, a specialist in causes ofAlzheimer's at the National Institute on Aging, Bethesda, Md. "A by-product is being created, and it has to be escorted out of the cell and disposed o£" When that pathway gets overwhelmed, the second pathway forms larger, less toxic Ap aggregates, presumably so the main pathway can catch up. Dillin, Kelly, and coworkers "have pulled together extant threads from other studies into a cogent hypothesis that lends itself to further testing in higher organisms," Snyder says. "The work shows that these pathways exist and to what extent they're used by the cell, and it points to therapeutics. It's a pretty important finding for the field." Chemistry professor Christopher M. Dobson of the University of Cambridge, in England, says the study "represents an extremely important advance in our understanding of Alzheimer's at a molecular level and, more generally, of all the neurodegenerative disorders linked to protein misfolding and aggregation. It marks a beginning of the
crucial process of discovering the underlying reason for one of the most characteristic features of these disorders—that they are unmistakably linked to the aging process." The work "provides important evidence to support the increasingly popular idea that the true culprits in Alzheimer's are the small aggregates that precede the large fibrils and plaques usually observed in the brains of patients," Dobson says. "It also presents strong evidence that diseases such as Alzheimer's result from the failure of mechanisms that normally protect against the inherent tendency of proteins to misfold and aggregate." Next step? Dillin and Kelly are trying to better understand the macromolecules that mediate aggregation and disaggregation. They're also pursuing small molecules that will delay aging and deter aggregationinduced neurotoxicity, and they already have some promising hits.—STU BORMAN Proteolysis - < > • Disaggregation
monomer
|SeoulamV*99r,sa"0" weight ^^* aggregate ^ «>^^
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DUAL PATH High-molecular-weight aggregate (less toxic) Dillin, Kelly, and coworkers discovered two neuroprotective pathways that may malfunction in Alzheimer's disease. One disassembles small toxic aggregates of Alzheimer's (^-peptide (A(3), and the other converts the small aggregates into less toxic larger ones.
C & E N / AUGUST U . 2006
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