May 21, 2002 -- (The New York Times News Service) -- 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 an 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 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 accumulate into insoluble deposits of protein called amyloid plaque.
Until recently, said Dr. Peter Lansbury, an associate professor of neurology at Harvard 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, 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, 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," 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 four 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. In each instance, the researchers said, the body eventually turns the protofibrils into sheets of fibrils called amyloid. The end result is plaque, which shows up inside tissues like boulders strewn on a landscape.
Alzheimer's disease is perhaps the best known protein misfolding disease, affecting 4 million Americans. As the disease progresses, plaque clusters made of a misfolded protein called "a-beta" accumulate in areas of the brain that control memory, mood and spatial awareness. The protofibril discovery may explain a longstanding mystery in Alzheimer's research, Klein said.
Autopsies on people who died in their 50s show that their brains are sometimes riddled with plaque and yet they were in no way demented. On the other end of the spectrum, a genetic mutation in some Swedish families leads to early onset of severe Alzheimer's disease, high levels of protofibrils but no plaque. Also, transgenic mice with human genes for a-beta protein contract a disease like Alzheimer's but without the plaque.
The explanation may lie in how fast protofibrils are turned into plaque, Cohen said. People who make plaque very quickly are protected from disease. Those who make plaque more slowly suffer a greater amount of cell damage.
Mutations can slow the process down in many ways. Having two copies of a gene called APOE-4 reduces how quickly a-beta is removed from a cell, Cohen said. "It's like having a flat tire on your garbage truck," he said.
May 24 (Bloomberg) -- Scientists have discovered a chemical reaction that may lead to degenerative brain diseases such as Parkinson's and Alzheimer's, a report says.
The reaction can block an enzyme needed for the proper folding of brain proteins, substances essential to life and health, scientists said today in the journal Nature. Proteins are chains of amino acids that must be folded into a particular shape to carry out their biological purposes.
When the enzyme doesn't work, improperly folded proteins can build up in the brain, leading to the injury and death of nerve cells, as occurs in the degenerative illnesses. Currently, no treatments have shown the ability to delay the onset of or cure either Parkinson's or Alzheimer's.
"If you could protect the enzyme, you might be able to stave off the diseases," said the leader of the study, Stuart Lipton, in a telephone interview.
To safeguard the enzyme, Lipton said, the key ingredient in the newly discovered chemistry would have to be stopped. That chemical is nitric oxide, an unstable molecule that can cause assorted chemical reactions, wreaking havoc.
Foiling the nitric acid might be possible with new medicines to be developed within a few years, said Lipton, 56, a neuroscientist and clinical neurologist at Burnham Institute for Medical Research in La Jolla, California. Lipton holds a patent on memantine, an Alzheimer's drug sold in the U.S. as Namenda by New York-based Forest Laboratories Inc.
Lipton's laboratory specializes in the molecular mechanisms of neurodegenerative diseases and stroke.
Both Parkinson's and Alzheimer's are characterized by protein accumulations, the researchers wrote. An enzyme called protein disulphide isomerase prevents cell damage and death from protein misfolding, according the study, while nitric oxide can interfere with the protective effect. Misfolded proteins can build up into plaques associated with illness.
While previous studies showed that nitric oxide can be involved in the degeneration of brain cells through a variety of mechanisms, the new study shows a previously unrecognized relationship between the chemical and protein misfolding, according to the authors.
About one of every 100 Americans over 65 has been diagnosed with Parkinson's, a movement disorder. The ailment caused almost 18,000 deaths in 2003, the latest year for which numbers are available, according to the National Center for Health Statistics, based in Hyattsville, Maryland.
No drug cures Parkinson's, and doctors disagree about whether any medicine slows the disease. Drugs do damp symptoms such as shaking in the hands, although the most common treatment, levadopa, can cause side effects such as limb writhing.
Alzheimer's, the most common form of senile dementia, afflicts some 20 million people worldwide. It accounted for more than 63,000 deaths in the U.S. in 2003, almost matching the combined total for influenza and pneumonia, according to the federal figures. There isn't any known cure, although drugs have improved cognitive function and memory in some patients, at least for a while.
Lipton and colleagues have developed several drugs, including memantine, to prevent cell damage or death due to excessive stimulation of the brain cells known as glutamate receptors.
