Old stain, new life
A traditional lab dye unexpectedly stabilizes proteins and extends lifespan in worms
A small molecule used to stain protein deposits actually stabilizes proteins and profoundly extends lifespan in worms, a new study in linkurl:Nature
| linkurl:C. elegans;http://commons.wikimedia.org/wiki/File:Enlarged_c_elegans.jpg |
Courtesy of the National Human
Genome Research Institute
The well-known laboratory dye could provide a starting point for a new class of therapeutics to slow the toxic aggregation of proteins in aging and diseases like Alzheimer's and Parkinson's disease.
"What makes this study beautiful is that science takes something old and reveals something new," said linkurl:Richard Morimoto,;http://groups.molbiosci.northwestern.edu/morimoto/index.html who studies misfolded proteins and cell stress at Northwestern University and was not involved in the research. "Instead of just detecting the fibers, this [dye] is perhaps telling us something about the dynamics" of protein aggregation, he added.
Amyloid-staining dyes like Congo red and Thioflavin T (ThT) are small molecules used regularly in histological techniques to stain proteins, especially in Alzheimer's research to visualize the amyloid beta plaques associated with the disease. "Nobody realized how biologically powerful these [dyes] are," said linkurl:Gordon Lithgow,;http://www.buckinstitute.org/Lithgowlab senior author on the paper at the Buck Institute for Research on Aging in Novato, California. "We got lucky and saw these amazing effects."
Four years ago, Silvestre Alavez, a postdoc in Lithgow's lab who had experience working with such dyes, began to suspect that they did more than simply light up amyloid. Testing a series of molecules in Caenorhabditis elegans,
Alavez found that ThT remarkably extended worms' lifespans by an average of 60 percent (see below videos). Several other ThT-like compounds also extended lifespan by up to 40 percent.
Control C. elegans, 20 days old, under normal conditions. The worms
present very limited movement and reduced body size associated
with the aging process in these nematodes.
Courtesy of Silvestre Alavez, Buck Institute
Worms treated with ThT after 20 days in culture. ThT treated worms
display a great improvement in motility and appearance consistent
with a delay in the aging process.
Courtesy of Silvestre Alavez, Buck Institute
To determine how the dyes were influencing lifespan, the team assessed the effect of ThT on protein homeostasis -- the maintenance of stable, properly folded proteins in a cell. Protein misfolding and the accumulation of proteins is associated with the aging process as well as neurodegenerative diseases like Alzheimer's and Parkinson's.
In the experiments, ThT reduced protein aggregation in vivo and even rescued aggregation-induced paralysis in two C. elegans
disease models. Knocking down a series of genes implicated in lifespan in C. elegans,
the team discovered a host of components, including molecular chaperones and proteaosomes, that work in concert to rid the cell of damaged or misfolded proteins and maintain homeostasis. Without those players, ThT had no effect.
"It seems like you need the whole system," said Lithgow. How ThT activates such pathways remains unclear, however. It is possible that by binding protein aggregates, the dye somehow initiates a signal in the cell to clean up misfolded or aggregated proteins, he said.
Lithgow is optimistic that ThT or other small molecules that act in the same way could provide a new approach to therapies for diseases involving protein aggregation. "We're a long way from a drug, but at least there's an idea here," said Lithgow.
The novel function of the dye should not affect experiments which currently use ThT or similar molecules, noted both Lithgow and Morimoto, since such dyes are typically used in test tubes and on dead tissue, where, without the cell's other machinery, they will not affect results.
Alavez, S., et al., "Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan," Nature, doi:10.1038/nature09873.
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[27th July 2009]
**__Related F1000 Evaluations:__***linkurl:Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions;http://f1000.com/7694957?key=4wmytbf41zq06vw
H. Olzscha et al., Cell
, 144:67-78, 2011. Evaluated by Sophie Jackson, Univ of Cambridge. *linkurl:Aromatic small molecules remodel toxic soluble oligomers of amyloid beta through three independent pathways;http://f1000.com/8649970?key=gn485123jyps35r
A.R. Ladiwala, et al., J Biol Chem,
286:3209-18, 2011. Evaluated by Werner Streicher, Dmitri Ermolenko and George Makhatadze, Rensselaer Polytechnic Institute.