Sci. Aging Knowl. Environ., 24 July 2002
Slow-aging mutants defer protein pileup that causes Huntington's disease
Key Words: polyQ huntingtin age-1
Abstract: Huntington's disease purloins its victims' coordination and sanity, clogging their brain cells with gobs of a protein called huntingtin. Although the cellular carnage is unstoppable in humans, a new study reveals that the toxic clumps accrue slowly in long-lived mutant worms engineered to produce the miscreant protein. The findings suggest that scientists might someday manage to delay the disease's progress by reviving cells' ability to discard tangled protein heaps.
Length matters in Huntington's disease. The huntingtin protein carries multiple copies of the amino acid glutamine at one end. People whose huntingtin contains fewer than 30 to 34 glutamines remain healthy, but individuals who make a variety with more than 35 to 40 are likely to die from the brain-wrecking illness. The extra glutamines make huntingtin proteins stickier, causing them to congeal into knots that poison cells. The more glutamines the protein sports, the earlier the symptoms begin.
To investigate what controls this protein clumping, Morley and colleagues genetically modified the muscle cells of Caenorhabditis elegans to make human huntingtin with up to 82 glutamines. Although worm muscle doesn't normally manufacture the protein, other studies have shown that the clumps can sprout and wreak havoc in cells other than neurons. As in people with Huntington's disease, protein globs accumulated in worms that produce huntingtin with more than 35 glutamines. Furthermore, the animals crawled half as fast as worms that made a protein toting fewer repeats, suggesting that the clumps cripple the modified muscle cells.
The researchers noticed that older animals amassed more of the huntingtin logjams. To find out if aging promotes clumping, they engineered long-lived mutant worms to produce huntingtin with 82 glutamines. Two days after hatching, these mutants sported 30% to 50% fewer tangles than did nonmutants of the same age, whose cells teemed with gunky clusters. The results suggest that the life-extending mutation somehow thwarts aggregation. The protection, however, was fleeting: By the age of 5 days, both mutants and nonmutants bore the same number of clumps. The study shows that formation of the ruinous clumps depends not just on the number of glutamines in the protein but also on something in the cell's internal environment, says Richard Morimoto, a molecular biologist at Northwestern University in Evanston, Illinois, and the paper's senior author. Although the mechanism remains unclear, the findings suggest that cells deploy defenses that either melt huntingtin masses or block their formation, says Morimoto.
Neurogeneticist J. Paul Taylor of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, calls the study "provocative," because it provides the first evidence that aging governs the accumulation of huntingtin clumps. As we grow older, our cells' ability to police their proteins might wane, Morimoto says. Restoring this vigilance could lead to treatments for the disease, although no one yet knows how. "We're not talking about preventing Huntington's, but you could delay it," Morimoto adds. That would give doctors the first weapon with which to cut this hereditary killer down to size.
--Mitch Leslie; suggested by Nick Bishop
J. F. Morley, H. R. Brignull, J. L. Weyers, R. I. Morimoto, The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A., 16 July 2002 [e-pub ahead of print]. [Abstract] [Full text]
Citation: M. Leslie, Procrastination Pays. Science's SAGE KE (24 July 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/29/nw100
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