In Folding Proteins, Clues to Many Diseases
By SANDRA BLAKESLEE
Published: May 21, 2002
Consider the consequences of a garbage strike. Trash accumulates, streets are clogged and daily life is disrupted. Eventually, things can come to a standstill.
Scientists say that kind of disruption may lie at the heart of a wide array of diseases afflicting millions of Americans.
In the brain, researchers say, the result is Alzheimer's disease, Parkinson's disease and a slew of other neurodegenerative disorders including the human version of mad cow disease. In the pancreas, it is Type 2 diabetes; in the lungs, cystic fibrosis; in the eyes, cataracts. If the problem develops in a certain blood protein, patients can develop numbness in the fingers or toes, or a mysterious form of heart disease that may affect as many as 4 percent of African-Americans.
In these and other diseases, researchers say, there are problems with the body's cellular machinery for making proteins and recycling misshapen proteins. Misfolded proteins build up, like trash clogging an alleyway.
Normally, our cellular machinery identifies misshapen proteins, reduces them to their constituent parts and recycles those parts. But when this process goes awry, small numbers of misfolded proteins accumulate into tiny spherical particles inside cells.
These particles are so small and soluble that they had escaped detection until very recently, but many researchers now say they may be what actually harms brain cells in Alzheimer's disease and islet cells in Type 2 diabetes and so on. Only later and gradually, however, the spheres stick together, forming tiny rods filaments and much larger fibrils, which in turn accumulate into insoluble deposits of protein called amyloid plaque.
Until recently, said Dr. Peter Lansbury, an associate professor of neurology at Harvard Medical School and the Brigham and Women's Hospital in Boston, researchers believed that the fibrils and plaque were themselves the bad actors, and they have been seeking medications and vaccines to remove them or block their formation.
But such therapies could make some diseases worse in that plaque removal might alter the kinetics of the system and hasten the rate of production of the toxic spheres.
The new picture of amyloid diseases evolved as physicists and chemists began using their research tools to understand exactly how proteins fold.
Proteins are strings of amino acids that bend naturally in helical loops, hairpin turns and pleated sheets. The final shape determines a protein's function in the body, so each string of amino acids must fold in exactly the right way. Potentially, though, strings can assume hundreds of millions of intermediate shapes on the way to their final form.
As many as a third of proteins end up misfolded, said Dr. Peter Wolynes, head of the structural biology program at the University of California at San Diego. These are what cells must eliminate and they have an elaborate machinery to do it, said Dr. Fred Cohen, a professor of medicine, pharmacology, biochemistry and biophysics at the University of California in San Francisco.
For example, protective molecules called chaperones form envelopes around proteins as they fold. In the crowded cell, chaperones help prevent partly folded proteins from bumping into other proteins that may try to swap elements or otherwise interfere with proper folding.
Once a protein is folded and ready to go to work, the chaperone pops off and finds another unfolded protein to protect, Dr. Cohen said. Chaperones can also grab misfolded intermediates and restart their folding process at the beginning.
A second system tags misfolded proteins with a molecule called ubiquitin and carries them to a garbage disposal -- a barrel-shaped structure called the proteosome. The proteosome is like a salami slicer, said Dr. Ron Kopito, an associate professor of biology at Stanford. It cuts up protein strings into constituent parts cells can recycle.
Many things can go wrong, Dr. Lansbury of Harvard said. Aging cells may not have the energy to run the proteosome or ubiquitin system. Toxins, inflammation and trauma can create imbalances. Some gene mutations result in so much extra production of a given protein that the body's removal system is overwhelmed.
''A certain amount of misfolding is fine,'' Dr. Cohen said. ''The cell can handle the trash. But if there's a garbage strike, the trash on the sidewalk begins to stink. That's what we're dealing with.''
What happens next is a subject of debate.
In the last few years, several laboratories around the world have detected the presence of tiny spheres of misfolded proteins, composed of anywhere from 4 to 30 protein molecules, in apparently healthy cells taken from people with diseases like Alzheimer's and Parkinson's. Many researchers believe these soluble spheres or protofibrils are injuring cells in a wide variety of diseases.
The details of how protofibrils may harm cells in the brain and other parts of the body are still being worked out, said Dr. William Klein, a professor of neurobiology and physiology at Northwestern University. One kind of protofibril seems to interfere with the process of memory consolidation, he said, and may explain why people experience mild cognitive impairment in middle age.
Other protofibrils appear to damage cells in the lung, heart, kidney, pancreas and other organs.