The implications of these studies have gone beyond polyglutamine diseases, as well. Many groups originally intrigued by inclusions have turned their attention away to focus on what they see as more likely pathogenic candidates. Greenberg discovered that by blocking ubiquitination of huntingtin, he prevented aggregation but increased cell death.
Huntingtin may simply clog the opening of the barrel, or exert its effect through a more circuitous route. According to this model, damage occurs when huntingtin or perhaps some other protein destined for recycling accumulates instead, setting off some other toxic chain of events. In this view, aggregation is a consequence of proteasomal dysfunction. Preventing aggregation, as Greenberg did, without repairing the proteasome, appears to increase the quantity of mutant huntingtin available to do its toxic mischief.
What mischief? One intriguing hypothesis relies on structural arguments about the polyglutamine itself. Its best-known proponent, until his death in early , was Max Perutz. Trained as a physicist, Perutz is revered as the father of molecular biology for his elucidation in of the structure of hemoglobin, for which he received the Nobel Prize three years later.
In the s, Perutz turned his attention to the polyglutamine diseases. He argued that the crucial similarity among the diseases was the threshold of approximately 37 to 41 glutamine repeats.
Below that, no disease occurred, above it, it always did. What damage might these tubes cause? Mitochondria are small, membrane-bound power generators in the cell, which use calcium to maintain a charge separation across their membranes. Prolonged loss of this potential triggers apoptosis cell suicide. What Greenamyre found was that long, but not short, polyglutamines directly associated with the mitochondrial membrane were preventing a balance in calcium and causing cell death.
Eventually, perhaps from accumulated dysfunction, perhaps from some acute stressful event, the cell death response is triggered. As exciting and intriguing as the polyglutamine tube scenario is, however, this is still only one of many competing hypotheses. Changes in the expression of these genes might cause the cell to be more sensitive to stress, less responsive to life-sustaining growth factors, or more likely to undergo apoptosis.
The unanswered question is whether any are, or whether these gene regulatory changes are epiphenomena in a cell dying for some other reason. A similar horse-and-cart question surrounds the involvement of caspases, enzymes that propel a sick cell along the apoptotic pathway. Mutant huntingtin activates caspases, but it is not clear whether this is an early event or a late one.
It is possible that all these hypotheses are partly correct, that each describes only one part of a still-hidden whole. This is the predicament of research on the edge of knowledge; the truth remains obscure, and all one has is the imperfect evidence.
In the meantime, experimental treatments are being developed or contemplated that are aligned with each pathogenic model, and the relative success of each treatment will likely advance or retard the relative standing of each model.
A case in point is minocycline, an antibiotic that is also a caspase inhibitor, that has slowed disease progression in mice. Some treatments have been tried, and have failed, already. Despite promising results in mice, neither creatine nor coenzyme Q10 is effective in patients; these nutritional supplements are thought to have antioxidant and mitochondria-boosting properties. Do they address the wrong problem, or are they just too little too late? Despite these early disappointments, most researchers believe that rational, effective treatments for HD are coming.
When they do, will they help patients who have already developed symptoms, or are such patients too far along in the disease process to be rescued? A remarkable series of experiments in mice has shown there is reason for optimism. These experiments, performed by Rene Hen, Ai Yamamoto, and colleagues at Columbia University, employed one of the newest and most remarkable tools in the molecular biology toolbox, the conditional promoter. In , they announced that mice that had expressed mutant huntingtin since birth, and that had already begun to develop inclusions and lose their motor coordination, got better when the gene was turned off: They became more coordinated, and their inclusions gradually cleared up.
If we can just shut off the gene, the brain might not only stop getting worse; it might be able to get better. How do you silence a gene?
This remains the major stumbling block for any gene-based HD therapy. It is too soon to know whether or how the huntingtin gene will be effectively silenced, but one last trick in the tool kit may be up to the job. Once in a cell, they link with and help destroy the RNA copy of their target gene before it can be turned into protein. While this proof of principle is reassuring, it is a very long way from cell culture to human therapies, and hundreds of treatments have stumbled along that path.
In this case, delivery getting the siRNA into the target cells is the main challenge, but effectiveness, toxicity, and side effects are also concerns that will have to be met by siRNA or any other therapy.
Are those who perform before the public—hundreds, thousands, even millions of spectators at a time—at heightened risk of mental illness? The Brain Prize went to four individuals whose independent research led to useful treatments for a disorder affecting a billion people. A sampling of work by Dana Simmons, Ph. However, it took a further 10 years to work out the exact location of the gene and to sequence its precise structure. A remarkable piece of scientific detective work revealed there are two versions of the gene.
A normal nonmutant version directs the manufacture of a protein called huntingtin, which we now know is involved in brain development. However, in some families a mutant version of this gene produces a toxic form of huntingtin. This accumulates in brain cells until it triggers the disease in mid-life.
Uncovering the precise nature of this pathway raised hopes that drugs could soon be developed to block the creation of mutant huntingtin. Indeed it has only been in the past few years that scientists have developed techniques to allow them to create drugs that can get into the brain. This is done via an injection that directly into the spinal fluid and is called a lumbar puncture. It is similar to that used to administer epidural pain relief during labour.
Fortunately we now have much better tools for tackling it. So I am hopeful we are going to move much faster. Previously, affected individuals were only spotted at the stage when their symptoms were manifesting themselves. Some researchers envisaged a future in which tests would be offered to at-risk men and women who were planning families. Those who registered positive would be persuaded not to have children. But this idea ignores the fact that many people from affected families are terrified they might die in the same grim fashion as their parents.
As a result, most people at risk of the disease choose not to have the test. And many genetic counsellors accept this decision, says Anna Middleton, head of society and ethics research at the Wellcome Genome Campus in Cambridge. The whole condition is a myriad of uncertainties.
People have to cope with so many factors — the experience of seeing the disease in relatives, the acceptance of uncertainty, and being able to live in the moment. Others do take the plunge, however.
For Matt Ellison it has meant being able to have a child, Joey — now 20 months old — with his partner Marianna. Mark Newnham also attempted to have children with his partner using the same technique, but without success. Drug RG is made up of a snippet of DNA, the material from which our genes are constructed, and it has been designed by scientists at Ionis Pharmaceuticals in Carlsbad, California.
In Tabrizi began a phase-one safety trial using the drug on 46 people with the disease and presented her results at a conference in March There were no harmful side-effects, she told delegates. More importantly she found that levels of mutant huntingtin were reduced in patients and, crucially, patients given the highest doses of RG saw the greatest reduction in levels of toxic protein.
The larger the number of triplet repeats, generally speaking, the earlier in life one will develop HD. Furthermore, when the gene is passed from father to child but not when passed from mother to child the gene may lengthen even more, resulting in an earlier age of onset for the disease. This phenomenon is known as anticipation. Genes for diseases can be either dominant or recessive. The gene for HD is dominant. On the other hand, if people with a parent suffering from HD do not inherit the mutant gene, they cannot pass it on to anyone else.
It is important to understand that while people are born with the mutated gene for HD, in most cases they will not develop the symptoms until later in life. Therefore someone can be without symptoms or presymptomatic for a number of years. In the past, there was no way to test for the abnormal gene, but now a blood test can determine whether or not an individual carries the gene for HD.
This test can be used in cases of suspected HD, to confirm the diagnosis, or it can be used as a predictive test in individuals who are at risk for HD. People who are at risk may want to undergo predictive testing in order to put their minds at ease, to plan for their medical needs, or prior to having children.
The decision to have such a test is a momentous one and should not be taken lightly. Most centers that do predictive testing, including ours, require a period of counseling before and after the test. Onset is usually in mid-life, but can occur any time from childhood to old age. The initial signs of this disorder may be subtle.
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