Huntington's

Trehalose and Huntington's                                         

Protein Stabilizer  A small molecule called trehalose that may help prevent protein aggregation. Everyone has a certain copy, or allele, of the Huntington gene, but people with Huntington’s disease (HD) have one copy that is longer than normal. The longer section of this HD allele consists of a repeated sequence, CAG, which codes for glutamine, an amino acid. Since the Huntington gene codes for the Huntington’s protein, the HD allele, with its extra CAG’s, codes for a Huntington’s proteins with too many glutamines. The extra glutamines cause the protein to have an abnormal shape, which prevents it from functioning, as it should. Instead, many of these altered Huntington’s proteins clump together and trap other useful and important molecules. These “clumps” are called protein aggregates, and they may prevent the normal functioning of nerve cells. Scientists are not sure if the formation of protein aggregates is a cause or only a symptom of HD, but many agree that it would be beneficial to prevent them from forming in the first place.

What is trehalose?  Trehalose is a disaccharide (two sugar) molecule composed of two smaller glucose molecules linked together. It is naturally produced by the body and can also be found in common foods. The U.S. Food and Drug Administration lists trehalose as a compound under the category of “generally regarded as safe.” Since trehalose is a sugar, it is used as a sweetener in products such as chewing gum. It also has a very important property that helps it to stabilize proteins and can thus be used as a biological preservative. It is this very feature that may useful for treating Huntington’s disease.

How can trehalose be used to treat HD?  A protein is made up of a string of amino acids. As the amino acids are strung together, the protein begins to fold up on itself until it gets to its final three-dimensional (3D) shape. Normal, stable proteins have no problem maintaining their shapes and functions in the cell. However, the Huntington’s proteins formed from the HD allele are not very stable on their own, so they form into clumps known as protein aggregation.

Scientists think that if these proteins can be stabilized before they are fully folded, the protein aggregations will not form. One research group set out to test just that idea. They found that disaccharides are good at stabilizing molecules with extra CAG repeats, and are therefore capable of preventing protein aggregation. Trehalose was the most effective stabilizer of all the disaccharides tested. The researchers think that trehalose works by binding directly to the glutamine repeat section (the extra part of the protein that usually makes it unstable), while leaving the normal proteins unaffected.

This initial success led the researchers to test trehalose in mice that have the mouse version of HD. (Trehalose was easily administered to the mice by putting the sugar in their drinking water.) The differences between the mice treated with trehalose and the untreated mice are thus far encouraging. According to these experiments, treated mice not only live longer than untreated mice, but also fewer of their nerve cells die. In addition, the treated mice walk more easily than untreated mice and they experience later onset of the physical symptoms associated with HD.

A word of caution  The prospect of using trehalose as a treatment for HD is very exciting because it is known to be generally safe and can be taken orally. However, there are many steps between an exciting prospect and an actual, safe treatment. Even if trehalose can be easily obtained in food or as a supplement, one should first consult a physician before taking trehalose to in hopes of treating HD. While the initial results are promising, we must remember that this was only one study conducted by one group, using mice as subjects, not humans. Trehalose has not even undergone the first stage of clinical trials. Moreover, the positive effects seen in mice do not guarantee that it will work or even be completely safe in humans with HD. Since trehalose is composed of glucose, some scientists think that it might be metabolised (broken down) before it can even get to the cells in the human brain. Others think that giving a treatment made of glucose could contribute to the already elevated risk of people with HD developing diabetes.

While the current study of trehalose in HD mice is an encouraging one, only future research will demonstrate its safety and effectiveness in treating HD in humans.

Diet and exercise work (here's how)

 The July 20, 2007 issue of Science published the results of research conducted at Children’s Hospital in Boston which provides one explanation for the benefits of improved eating habits and exercise on life span.  

Working with mice, Akiko Tachi, PhD, Lynn Wartschow, and Morris White of Harvard demonstrate that reducing insulin receptor substrate-2 (Irs-2) signaling increases life span as well as brain levels of superoxide dismutase, a protective antioxidant enzyme. Acting on the basis of previous research in roundworms and fruit files which found an increase in life span associated with a reduction in insulin signaling, the trio engineered mice to reduce the amount of Irs-2, a protein that carries the insulin signal inside the cell, by half. Because reducing insulin signaling can cause diabetes, the researchers tested their hypothesis that reducing insulin signaling just in the brain, but not the rest of the body, would result in an increase in life span. They engineered two groups of animals to experience a reduction in Irs-2 in their brains alone, while one group of animals was engineered to have lower Irs-2 in all cells, and another group served as controls. 

“To our surprise, all of the engineered mice lived longer,” Dr Taguchi remarked. Despite being overweight and having higher insulin levels, animals with diminished brain insulin signaling experienced an 18 percent increase in lifespan compared to the normal controls. The mice were also more active and retained greater levels of superoxide dismutase in old age.  

“The idea that insulin reduces lifespan is difficult to reconcile with decades of clinical practice and scientific investigation to treat diabetes,” Dr White noted. “The engineered mice live longer because the diseases that kill them – cancer, cardiovascular disease and others – are being postponed by reducing insulin-like signaling in the brain regardless of how much insulin there is in the rest of the body. The easiest way to keep insulin levels low in the brain is old-fashioned diet and exercise.”  

“Our findings put a mechanism behind what your mother told when you were growing up—eat a good diet and exercise, and it will keep you healthy,” White observed. “Diet, exercise and lower weight keep your peripheral tissues sensitive to insulin. That reduces the amount and duration of insulin secretion needed to keep your glucose under control when you eat. Therefore, the brain is exposed to less insulin. Since insulin turns on Irs2 in the brain, that means lower Irs2 activity, which we’ve linked to longer lifespan in the mouse.”

 “We are beginning to appreciate that obesity, insulin resistance, and high blood insulin levels are connected to Alzheimer’s disease, Huntington’s disease, and dementias in general,” he added. “It might be that, in people who are genetically predisposed to these diseases, too much insulin overactivates Irs2 in the brain and accelerates disease progression. Thus, insulin resistance and higher insulin levels might be the environmental influences that promote these diseases.”

From Dr Hoffer on Individuality -

Roger Williams showed that humans are not alike biochemically and that their nutritional needs are not identical. He showed scientists what we all knew: that we are all individual. We do not have the same fingerprints, the same blood types; we do not look alike, think alike or suffer alike. Why, then, would the early nutritionists think that we are alike in terms of the nutrients we need? The RDAs recognized that we are not alike and made a minor provision for this by recommending slightly higher doses than they actually thought we needed. But the range of doses they recommended were altogether too restricted as they were not based on large population studies but were arrived at from animal studies and by guess, using normal amounts in food as the basic guide. In reality, the range of need is much greater than was recognized, and is much greater than is recognized by the health professions today.

Essentially genes determine what our nutritional needs are. We cannot turn our genes into new ones and so have to be content with what we have, but we can feed them much more effectively. As I see it, there are no defective genes in individuals who are born normal and are normal for some time; if the genes really were defective they would have been eliminated long time ago by the process of evolution. If a person has been healthy and productive for 70 years and then develops Alzheimer’s disease, how can one blame the genes that had served so well for such a long time? But something has happened. Genes must have the correct internal biochemical environment, and if this is not provided they will not function properly. This suggests that any disease which develops later in life is caused by genes that are no longer being looked after properly; by this I mean they are not being fed properly. Diseases which are apparently genetic, like Huntington’s disease, are therefore not untreatable. We still have not looked for the factors in the gene’s environment that are lacking. The few patients I have treated with this disease recovered when given large doses of vitamin E and niacin. I have suggested that families with the gene ought to take these vitamins as a measure to prevent the development of the disease. One day we will have laboratory tests that will determine what the genetic needs are.

Bruce Ames in his wide ranging review of enzymes and the need for increased vitamin intakes concludes that as many as one-third of mutations in a gene result in the corresponding enzymes having a decrease in binding affinity of a coenzyme resulting in lower rates of reactions. These defects can be helped by high doses of the correct vitamins. He listed more than fifty genetic diseases successfully treated with high doses of vitamins. The high doses of the vitamins forces the reaction that is being catalyzed by too little coenzyme. He estimated that a very small proportion of all these genetic disorders have been discovered.

It is very unlikely that all single vitamin dependencies have been recognized. But as the modern foods become more and more deficient in overall nutrients, these will begin to show more and more. In1950 when I first started to practise psychiatry there were very few children recognized as being hyperactive or having a hyperactivity/learning disorder, one of the forty modern diseases described by psychiatry in DSM IV. Today up to 10 percent of the children of any classroom may carry this diagnosis. The main change has been the gradual deterioration of our national diets.

There is no reason why some individuals will not have multiple dependency conditions. Huntington's disease is an example of a double dependency on niacin and on vitamin E. I thought that multiple dependencies (more than two) will be even rarer but I was wrong.

There is one condition which is dependent on four nutrients. This is AIDS: HIV/AIDS is treatable by four important nutrients, the mineral selenium and the three amino acids tryptophan, cysteine and glutamine. These are components of glutathione peroxidase the essential compound that is lacking.

For More information about Motor Neuron Disease (MND) please see Steve Shackel’s site.