Small clumps of misfolded protein wreak havoc.
Alzheimer's disease may be caused by small clumps of wrongly folded proteins, two new studies suggest. Stopping rogue proteins ganging up might prevent or reverse this and other diseases, including diabetes and CJD.
Dennis Selkoe of Harvard Medical School, Boston, and his colleagues have found that clumps of just a few molecules of misfolded amyloid beta protein hinder memory processes in rat brains1. These clumps, called oligomers, stick to and disrupt synapses, the junctions where nerve cells communicate with one another.
Scientists have long known that large clusters of amyloid beta accumulate in the brains of Alzheimer's patients. But the links between the protein and dementia are not clear. The new results provide a clue. "We've put a smoking gun in the hand of the amyloid beta oligomer," says Selkoe.
"It's an exciting and significant finding," says Mark Pepys, who studies protein-folding diseases at the Royal Free Hospital, London. "It strongly suggests a possible way in which amyloid beta causes neuronal damage."
Selkoe's team also found that chemical blockers of the enzyme that makes amyloid beta prevent oligomers forming in cell culture. Such cells continue functioning normally.
Several pharmaceutical companies are developing drugs based on these blockers, which are called gamma-secretase inhibitors. Selkoe believes that products to prevent and possibly treat Alzheimer's in this way could be on the market in 5-7 years.
Chain of events
Proteins are long chains that twist up into blobs shaped to fit their function. Normally their water-loving parts are on the outside, making them soluble, and their water-repellent parts are tucked inside out of harm's way. If a protein folds up wrongly, exposing its water-repellent parts, it comes out of solution and forms clumps in the cell or tissue.
“>Small aggregates might be the common factor that links protein-folding diseases Christopher Dobson, , University of Cambridge”
So, incorrectly folded proteins can be toxic. Christopher Dobson of the University of Cambridge and his colleagues persuaded two harmless proteins, one from bacteria and the other from cattle, to change shape. Small clumps of both new forms weakened mouse cells2.
Dobson's team could have discovered a general principle behind diseases as diverse as type II diabetes, CJD and Alzheimer's. Small aggregates "might be the common factor that links protein-folding diseases," he says.
In all these diseases, large bundles of insoluble protein build up. Smaller groups that form along the way would be more mobile and might barge around the cell interfering with other proteins.
"It's interesting and intriguing," says Pepys. But, he cautions, there's a limit to how much heavily manipulated proteins and cells in culture can tell us about the complex real world. "It's still a long way from elucidating how misfolded proteins cause disease."
Walsh, D. M. et al. Naturally secreted oligomers of amyloid (protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535 - 539 (2002).
Bucciantini, M. et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507 - 511 (2002).
University of Cambridge