# garbage dump syndromes



## trbell (Nov 1, 2000)

this is from the NYTimes and might be of interest soon. http://www.nytimes.com/2002/05/21/health/2...012000m5Il$5GID tom


----------



## squrts (Aug 14, 2000)

i didnt get an artical,only a sign up page.


----------



## trbell (Nov 1, 2000)

may have to sign up first (it should be free) and then copy the url and paste it into your browser.tom


----------



## Susan Purry (Nov 6, 2001)

Tom, would it be at all possible for you to cut and past the article as I don't want to provide personal info for signing up. Thanks. If you can't, don't worry. susan p.sI think it's ok regarding copyright if you put it in quotes and paste the URL.


----------



## trbell (Nov 1, 2000)

This article from NYTimes.com has been sent to you by trbell###comcast.net./-------------------- advertisement -----------------------Enjoy new investment freedom!Get the tools you need to successfully manage your portfoliofrom Harrisdirect. Start with award-winning research. Thenadd access to round-the-clock customer service fromSeries-7 trained representatives. Open an account today andreceive a $100 credit! http://www.nytimes.com/ads/Harrisdirect.html ----------------------------------------------------------/In Folding Proteins, Clues to Many DiseasesMay 21, 2002By SANDRA BLAKESLEE Consider the consequences of a garbage strike. Trashaccumulates, streets are clogged and daily life isdisrupted. Eventually, things can come to a standstill. Scientists say that kind of disruption may lie at the heartof a wide array of diseases afflicting millions ofAmericans. In the brain, researchers say, the result is Alzheimer'sdisease, Parkinson's disease and a slew of otherneurodegenerative disorders including the human version ofmad cow disease. In the pancreas, it is Type 2 diabetes; inthe lungs, cystic fibrosis; in the eyes, cataracts. If theproblem develops in a certain blood protein, patients candevelop numbness in the fingers or toes, or a mysteriousform of heart disease that may affect as many as 4 percentof African-Americans. In these and other diseases, researchers say, there areproblems with the body's cellular machinery for makingproteins and recycling misshapen proteins. Misfoldedproteins build up, like trash clogging an alleyway. Normally, our cellular machinery identifies misshapenproteins, reduces them to their constituent parts andrecycles those parts. But when this process goes awry,small numbers of misfolded proteins accumulate into tinyspherical particles inside cells. These particles are so small and soluble that they hadescaped detection until very recently, but many researchersnow say they may be what actually harms brain cells inAlzheimer's disease and islet cells in Type 2 diabetes andso on. Only later and gradually, however, the spheres sticktogether, forming tiny rods filaments and much largerfibrils, which in turn accumulate into insoluble depositsof protein called amyloid plaque. Until recently, said Dr. Peter Lansbury, an associateprofessor of neurology at Harvard Medical School and theBrigham and Women's Hospital in Boston, researchersbelieved that the fibrils and plaque were themselves thebad actors, and they have been seeking medications andvaccines to remove them or block their formation. But such therapies could make some diseases worse in thatplaque removal might alter the kinetics of the system andhasten the rate of production of the toxic spheres. The new picture of amyloid diseases evolved as physicistsand chemists began using their research tools to understandexactly how proteins fold. Proteins are strings of amino acids that bend naturally inhelical loops, hairpin turns and pleated sheets. The finalshape determines a protein's function in the body, so eachstring of amino acids must fold in exactly the right way.Potentially, though, strings can assume hundreds ofmillions of intermediate shapes on the way to their finalform. As many as a third of proteins end up misfolded, said Dr.Peter Wolynes, head of the structural biology program atthe University of California at San Diego. These are whatcells must eliminate and they have an elaborate machineryto do it, said Dr. Fred Cohen, a professor of medicine,pharmacology, biochemistry and biophysics at the Universityof California in San Francisco. For example, protective molecules called chaperones formenvelopes around proteins as they fold. In the crowdedcell, chaperones help prevent partly folded proteins frombumping into other proteins that may try to swap elementsor otherwise interfere with proper folding. Once a protein is folded and ready to go to work, thechaperone pops off and finds another unfolded protein toprotect, Dr. Cohen said. Chaperones can also grab misfoldedintermediates and restart their folding process at thebeginning. A second system tags misfolded proteins with a moleculecalled ubiquitin and carries them to a garbage disposal - abarrel-shaped structure called the proteosome. Theproteosome is like a salami slicer, said Dr. Ron Kopito, anassociate professor of biology at Stanford. It cuts upprotein 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 proteosomeor ubiquitin system. Toxins, inflammation and trauma cancreate imbalances. Some gene mutations result in so muchextra production of a given protein that the body's removalsystem is overwhelmed. "A certain amount of misfolding is fine," Dr. Cohen said."The cell can handle the trash. But if there's a garbagestrike, the trash on the sidewalk begins to stink. That'swhat we're dealing with." What happens next is a subject of debate. In the last fewyears, several laboratories around the world have detectedthe presence of tiny spheres of misfolded proteins,composed of anywhere from 4 to 30 protein molecules, inapparently healthy cells taken from people with diseaseslike Alzheimer's and Parkinson's. Many researchers believethese soluble spheres or protofibrils are injuring cells ina wide variety of diseases. The details of how protofibrils may harm cells in the brainand other parts of the body are still being worked out,said Dr. William Klein, a professor of neurobiology andphysiology at Northwestern University. One kind ofprotofibril seems to interfere with the process of memoryconsolidation, he said, and may explain why peopleexperience 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 eventuallyturns the protofibrils into sheets of fibrils calledamyloid. The end result is plaque, which shows up insidetissues like boulders strewn on a landscape. Alzheimer's disease is perhaps the best known proteinmisfolding disease, affecting four million Americans. Asthe disease progresses, plaque clusters made of a misfoldedprotein called "a-beta" accumulate in areas of the brainthat control memory, mood and spatial awareness. The protofibril discovery may explain a longstandingmystery in Alzheimer's research, Dr. Klein said. Autopsies on people who died in their 50's show that theirbrains are sometimes riddled with plaque and yet they werein no way demented. On the other end of the spectrum, a genetic mutation insome Swedish families leads to early onset of severeAlzheimer's disease, high levels of protofibrils but noplaque. Also, transgenic mice with human genes for a-betaprotein contract a disease like Alzheimer's but without theplaque. The explanation may lie in how fast protofibrils are turnedinto plaque, Dr. Cohen said. People who make plaque veryquickly are protected from disease. Those who make plaquemore slowly suffer a greater amount of cell damage. Mutations can slow the process down in many ways. Havingtwo copies of a gene called APOE-4 reduces how quicklya-beta is removed from a cell, Dr. Cohen said. "It's likehaving a flat tire on your garbage truck," he said. Parkinson's disease shows similar characteristics. Aprotein called alpha-synuclein misfolds and aggregates inthe brain in plaques called Lewy bodies. Protofibrils ofsynuclein have been detected in patients' cells and appearto be toxic. Certain genes and environmental factors, likeexposure to a pesticide called rotenone, ultimatelyincrease the misfolding process. Still unexplained with Parkinson's disease is the reasonthat cells that make dopamine, a neurotransmitter involvedin movement and decision making, suffer the most damage,Dr. Lansbury said. Part of the answer may be that dopamineand synuclein have been shown to react with each another.When this happens, protofibrils convert to fibrils at aslower rate. The result, he said, is that toxicprotofibrils accumulate and harm dopamine-producing cells. The primary therapy for early stage Parkinson's disease isto give patients more dopamine, Dr. Lansbury said. Buthaving more dopamine may mean causing more protofibrils toaccumulate. Instead of helping, the dopamine-replacementtherapy may speed the disease progression. Fortunately,some dopamine-enhancing drugs do not react with synucleinand can avoid this problem, Dr. Lansbury said. Misfolded proteins are also behind the spongiformencephalopathies, diseases that involve strange, spongelikeholes tin certain parts of the brain. The human form isCreutzfeldt-Jakob disease; in cattle it is mad cow disease;in sheep, scrapie; and in deer and elk, chronic wastingdisease. In each case the misfolded protein is called a prion. Whiletoxic protofibrils of prions have not been detected, manyscientists believe that disruptions in the trash removalsystem are at fault. Moreover, studies of prion diseasesare shedding light on how seeds of misfolded proteins cancorrupt otherwise healthy proteins and propagate disease. Now, some researchers are linking a growing list ofconditions to misfolded proteins. Huntington's disease andA.L.S. (amyotrophic lateral sclerosis or Lou Gehrig'sdisease) also appear to be protein misfolding disorders.Blood can carry misfolded proteins. A plasma protein calledtransthyretin often misfolds into amyloid because of atleast 80 mutations affecting different parts of the body.Some mutations lead to plaque buildup in the hands, feet,liver or heart, said Dr. Jeffrey Kelly, a chemist at theScripps Research Institute in La Jolla, Calif. Some experts believe that a transthyretin mutation commonin African-Americans leads to a form of heart disease thatis difficult to diagnose. Type 2 diabetes is also anamyloid disease. A hormone called islet amyloid polypeptide, or IAPP, isreleased along with insulin by cells in the pancreas. Thehormone produces protofibrils, which then collect intolarger fibrils, said Dr. Per Westermark, a professor ofgenetics and pathology at the University of Uppsala inSweden. Affected islet cells produce less insulin, therebyworsening the disease. The researchers say they hope a deeper understanding of howthe body's trash removal system fails will lead them totherapies 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 ofthese really insidious diseases." http://www.nytimes.com/2002/05/21/health/2...eda33ca06ee1941 HOW TO ADVERTISE---------------------------------For information on advertising in e-mail newslettersor other creative advertising opportunities with TheNew York Times on the Web, please contactonlinesales###nytimes.com or visit our online mediakit at http://www.nytimes.com/adinfo For general information about NYTimes.com, write to help###nytimes.com. Copyright 2002 The New York Times Companytom


----------

