PROTEIN FOLDING IMPORTANT FOR GOOD HEALTH
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 each case the misfolded protein is called a prion. While toxic protofibrils of prions have not been detected, many scientists believe that disruptions in the trash removal system are at fault. Moreover, studies of prion diseases are shedding light on how seeds of misfolded proteins can corrupt otherwise healthy proteins and propagate disease.
Now, some researchers are linking a growing list of conditions to misfolded proteins. Huntington's disease and A.L.S. (amyotrophic lateral sclerosis or Lou Gehrig’s disease) also appear to be protein misfolding disorders. 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. A certain amount of misfolding is fine. '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.
Blood can carry misfolded proteins. A plasma protein called transthyretin often misfolds into amyloid. Some mutations lead to plaque buildup in the hands, feet, liver or heart. Some experts believe that a transthyretin mutation common in African-Americans leads to a form of heart disease that is difficult to diagnose. Type 2 diabetes is also an amyloid disease.
A hormone called islet amyloid polypeptide, or IAPP, is released along with insulin by cells in the pancreas. The hormone produces protofibrils, which then collect into larger fibrils; affected islet cells produce less insulin, thereby worsening the disease
The researchers say they hope a deeper understanding of how the body's trash removal system fails will lead them to therapies for many currently untreatable diseases. ''If we could slow down the process by just 10 years,'' Dr. Cohen said, ''millions of people might escape the ravages of these really insidious diseases.''
Many unrelated diseases as Alzheimer’s; mad cow disease; cystic fibrosis and many caners apparently result from protein folding gone wrong. Misfolded prions force healthy prions to misfold also. They are infectious. If a person or animal eats misfolded prions, a disease is transmitted. Misfolded cow prions appear capable of commandeering prions in many different species, including humans.
Alzheimer's disease is perhaps the best known protein misfolding disease, affecting four 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.
Proteins are fundamental parts of all living cells. The plants and animals we eat and bacteria that infect us all have proteins. Hemoglobin, insulin, our antibodies that fight disease, the myosin in our muscles that make our muscles contract, the tendon and ligaments and even much of our bones all are proteins.
Proteins string together in long chains, like shoelaces, and loop around each other in various ways like folding. As a knotted shoelace, a misfolded protein can poison the cells around it. Sometimes the protein will fold into a wrong shape. Some proteins named chaperones block these proteins from folding wrong.
We recently found that proteins can unfold wrong. When we boil an egg, the proteins in the white unfold. As the egg cool the proteins don’t bounce back to their original shapes, but form a solid mass. This is unfolding.
To deal with this problem, cells have evolved an elaborate machinery for tagging and moving misfolded proteins to a kind of garbage disposal system where chains of amino acids are chopped up and recycled. Quality control is so important that thousands of specialized proteins, called chaperones, carry out the recycling task.
But as people age, their garbage disposal systems break down. The result is that misfolded proteins accumulate into gunk that can be benign or toxic. We can now study these masses of proteins.
For over a hundred years we knew certain diseases have proteins deposited in certain tissues. Also, Alzheimer noted tangles and plaques in his patient’s brain. Tangles are common in disease that have nerve cell death. Plaques, which are specific for Alzheimer’s, are not common. Does the disease cause plaques or is it the result of the disease?
These nerve plaques are composed of only one protein. (These plaques are unrelated to plaques in blood vessels that cause heart attacks.) Plaques that are partially folded chains fold in seconds. But they have an important role in folding. It seems the partially folded proteins do the tangling, not the fully folded proteins.
Alzheimer’s affects 10% of people over 65 and perhaps half of those over 85. It kills 100,000 Americans and costs us $83 billion to care for its victims.
A fat transporting protein called apoE2 transports cholesterol and fatty materials in the blood are found in Alzheimer’s patients. It could be a pathogenic chaperone that promotes misfolding, but many scientists think the apoE2 is a normal chaperone and has a protective effect.
Infectious diseases transmitted by prions or protein particles, cause a protein folding disorder. It is seen in Creutzfeldt-Jacob disease, (human mad cow disease), scrapie in sheep and mad cow disease in cows. Prions are proteins. Proteins are made by genes that determine how the molecules that make up proteins, called amino acids, are arranged. A newly synthesized protein is a floppy string of amino acids. Based on how it is strung, with positive and negative forces bumping into each other, each protein folds itself into a three-dimensional shape. A protein's shape determines its function, in the way that keys fit into locks.
Prions are pure protein and don’t have DNA nor RNA. But how then can they reproduce themselves. The prion protein acts as its own chaperone. A small amount of protein misfolds and becomes a prion. As it bumps into a normal folding protein it shifts the folding process. As the prions accumulate of toxic insoluble gunk, there is not enough normal proteins to do the job properly. It seems there is a lack of a protein that regulated chloride transport. If the final step in normal folding cant occurs, the normal protein can’t be produced.
Most cancers result from mutation in the genes that regulate cell growth and division. Over 40%of cancers have the p53 protein to prevent cells that have damaged DNA from dividing and prevent cells from becoming cancerous.
One p53 mutation keeps the protein from binding to DNA: another makes the folded protein less stable. In the latter, there is never enough properly folded protein to block the damaged DNA cells from dividing.
The key to treatments for these disease is to find a small molecule that can stabilize the normal folding or will disrupt the pathway of the misfolded protein. Most proteins so not have a small molecule binding site. Stabilizing p53 may be another way.
Source; Journal NIH Research Hooper,3 (April 65-76)
Taubes, Science 271 (1493-95)
Visit me @ www.drneedles.com for more provocative medical information. And as always, your comments are appreciated.
No comments:
Post a Comment