Tangled web. Under the right conditions, normal proteins can form toxic amyloid fibrils

Harmless Proteins Twist Into Troublemakers

Some proteins are known contortionists; they bend and fold and stick together, contributing to neurodegenerative diseases such as Alzheimer's. Now researchers report the startling news that all sorts of proteins can perform the same devilish tricks in the lab. The findings, discussed at a National Academy of Sciences colloquium in Washington, D.C., on 23 March and reported in the 3 April issue of Nature, hint that a certain type of misfolding may be common to all proteins, although researchers caution that the work has been limited to extreme conditions within test tubes.

About 20 proteins share the ability to clump together to form distinctive "amyloid fibrils" that contribute to Alzheimer's, Creutzfeldt-Jakob disease, and a variety of lesser-known disorders. Chris Dobson, a chemist and structural biologist at the University of Cambridge, U.K., suspected that a much broader range of proteins could form amyloid fibrils in test tubes.

Dobson's team has experimented with roughly a dozen common proteins with a variety of structures and functions found in humans, plants, or yeast. Thus far, each one has proved capable of forming fibrils when heated or immersed in a solution containing acid or a form of alcohol. Even the oxygen transport protein myoglobin underwent a complete structural overhaul and adopted a fibrillar form. The lab-induced transformations may be as deadly as the misfolding of disease-related proteins. The researchers tested the effects of two of their manipulated proteins on mouse and rat cells. Products from an early stage of fibril formation were even more toxic to cells than the final, fibrillar form--just as some researchers suspect is the case for early stages of protein misfolding in Alzheimer's disease.

What this all means is yet to be determined. A small but growing cohort of scientists suspects that if this style of misfolding is a generic property of proteins, it's likely to play a role in normal biology. "My view is that there are some cases where these kinds of transitions are beneficial," says Susan Lindquist, a molecular biologist and director of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

Related sites
Colloquium overview
Dobson's site
Background on protein folding

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