Tail of the Gene Tells the Tale of Machado-Joseph Disease
The repetition of three little “letters” within the gene that codes for the ataxin-3 protein is both the cause of and perhaps a solution to Machado-Joseph disease (MJD) and an entire family of similar genetic disorders, according to researchers at Penn. Their findings, which appeared in the March 31 journal Molecular Cell, present a potential therapeutic role for the ataxin-3 protein for MJD and related disorders such as Huntington’s disease.
Machado-Joseph disease is among the most common of the nine known polyglutamine repeat disorders, a family of diseases in which the genetic code for the amino acid polyglutamine CAG becomes excessively repeated within the gene, making the protein toxic. In these diseases, the expanded polyglutamine domain causes the errant protein to fold improperly, which causes a glut of misfolded protein to collect in tissues of the nervous system, much like what occurs in Alzheimer’s and Parkinson’s diseases.
“In origami, if you misfold the paper, you can just throw the paper into the recycling bin,” said Dr. Nancy Bonini, professor of biology and Howard Hughes Medical Institute investigator. “If a protein misfolds, cells rely on their own recycling system to dispose of it. It turns out that ataxin-3 may influence this system, especially for recycling those that have misfolded due to excessive polyglutamine repeats. Our findings show that ataxin-3 not only blunts the toxicity of mutant versions of itself but can also mitigate neurodegeneration induced by other such mutant polyglutamine proteins.”
Machado-Joseph disease is among the most common dominantly inherited ataxias, a neurodegenerative disorder marked by a gradual decay of muscle control. MJD typically appears in adulthood, with a longer repeat expansion being associated with earlier onset and more severe disease. Its symptoms, uncoordinated motor control, worsen with time.
To study just how the ataxin-3 protein relates to disease, Dr. Bonini and her colleagues worked in a simple model organism, the fruit fly, engineering flies to express both the normal human ataxin-3 protein and a toxic human disease form of ataxin-3 with an expanded polyglutamine repeat. When both genes are in the same fruit fly, however, the functioning gene helps protect against the effects of the bad one. Their studies demonstrated that the protective function of the ataxin-3 protein does not rely on the multiple repeats in its tail but in a region near the head. Indeed, it seems that removing or altering this region of the gene can accelerate the progress of the disease.
Cognitive Therapy Works As Well As Antidepressants
Cognitive therapy to treat moderate to severe depression works just as well as antidepressants, according to an authoritative report appearingin the April 4 issue of Archives of General Psychiatry. The study, conducted by researchers at Penn and Vanderbilt University, conclude that cognitive therapy was more effective than medication at preventing relapses after the end of treatment.
The study involved 240 depressed patients who were randomly placed into groups that received cognitive therapy, antidepressant medication or a placebo. Patients in the antidepressant group, which was twice as large as the other two, were treated with paroxetine (Paxil). Lithium or desipramine was also given, as necessary.
After 16 weeks of treatment, patients in both the medication and cognitive therapy groups showed improvement at about the same rate; however, cognitive therapy patients were less likely to relapse in the two years following the end of treatment. According to the researchers, the return of symptoms might demonstrate that the medication may have blunted the appearance of depression but did not affect underlying disease processes.
“Medication is often an appropriate treatment, but drugs have drawbacks, such as side effects or a diminished efficacy over time,” said Dr. Robert DeRubeis, professor and chair of the department of psychology. “Patients with depression are often overwhelmed by other factors in their life that pills simply cannot solve. In many cases, cognitive therapy succeeds because it teaches the skills that help people cope.”
The researchers also noted slight differences in the response to treatment between the two testing locations, with cognitive therapy performing better at Penn and medications performing better at Vanderbilt. Researchers surmise that the medication worked so well at the Vanderbilt clinic because more of the patients there were markedly anxious, in addition to being depressed, and the medications used in the research have anti-anxiety properties.
The researchers further believe that cognitive therapy patients might have done better at Penn due to the experience level of the therapists involved. Just as the experience of therapists may be important in cognitive therapy, so, too, can the expertise of prescribing physicians play a role in the success of antidepressant medication treatment. Studies have shown that antidepressant medication dosages are still largely a matter of physicians’ discretion.
Mouse Model for MSA Points to Treatment for Brain Diseases
A newly developed animal model for Multiple System Atrophy (MSA) –a collection of neurodegenerative disorders once thought to be three separate diseases–sheds new light on this little-studied brain disease, according to research from investigators at the School of Medicine.
Dr. Virginia M.-Y. Lee, director of Penn’s Center for Neurodegenerative Disease Research, and her colleagues demonstrated that the mice showed symptoms similar to human MSA. These include an accumulation of a protein called a-synuclein in oligodendrocytes–cells that produce the protective myelin sheath that covers axons. This protein accumulation disables oligodendrocytes, leading to a loss of the sheath on neurons and eventually nerve-cell malfunction and death. The mice also showed slowly progressive problems with their motor skills associated with the nerve-cell damage.
“The uniqueness of this disease is that, unlike most of the neurodegenerative diseases, which affect neurons primarily and oligodendrocytes secondarily, this is the other way around,” said Dr. Lee. In fact, there is growing evidence that non-neuronal cells also play a role in amyloid deposits in Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) mouse models. Dr. Lee and her colleagues reported their findings in the March 24, 2005 issue of Neuron.
MSA is so named because it affects multiple parts of the nervous system. Initially MSA was given three names based on the symptoms physicians had observed. However, when they closely examined patients’ pathology, the disorders seemed related, based on the a-synuclein proteins in cells. In the clinic, many patients with MSA present symptoms similar to Parkinson’s disease, and MSA has been misdiagnosed as such.
Collectively, MSA now includes three related disorders characterized by their most prominent symptoms: olivopontocerebellar atrophy, which affects balance, coordination and speech; striatonigral degeneration, the closest to Parkinson’s disease because of slow movement and stiff muscles; and Shy-Drager syndrome, which involves altered bowel, bladder and blood-pressure control. Other general symptoms include dizziness, impaired speech, breathing and swallowing difficulties, and blurred vision. Most patients develop dementia late in the course of disease, which is usually diagnosed in people over 50 years old.
Unchecked DNA Replication Drives Steps Toward Cancer
Although not widely appreciated as a disease of the genes, cancer is rooted in genetic errors or problems in gene regulation. Scientists have identified some of the first genetic triggers for cancer as mutations in specific oncogenes or tumor suppressor genes. Full-blown tumors and metastatic cancers, however, often exhibit many genetic mutations, sometimes dozens in a given tumor. An important scientific question asked has been what happens after the initial mutation that leads to dangerous later-stage cancers with multiple damaged genes.
In a new study, researchers at The Wistar Institute answer this vital question and suggest why mutations in a certain few genes, such as the p53 tumor suppressor gene, are found in so many different cancers. The Wistar team’s primary observation is that an initiating genetic error can push a cell to divide relentlessly, leading to conditions of DNA replication stress. This stress leads to random errors in the DNA duplication process. Unless halted, this error-generating process leads to an accumulation of mutant genes in the cell and, eventually, cancer.
“Scientists have debated for a long time whether very early precancerous cells are genetically unstable, whether they have an unusually high mutation rate. What we show in this study is that they do have a higher mutation rate than normal through this mechanism,” says Dr. Thanos D. Halazonetis, professor in the molecular and cellular oncogenesis program at Wistar and senior author on the Nature study.
Fortunately, cells have an effective on-board damage control system, managed by the p53 gene. A protein called 53BP1 senses the DNA breaks caused by replication stress and activates the p53 pathway. That pathway shuts down the replication process, thus limiting further DNA damage. In some circumstances, p53 may even force the cell into apoptosis, or programmed death, as a way to protect against the cell developing into a tumor.
If the mutations occur in p53 itself, however, or the p53 pathway is unable to completely halt the process, further mutations will occur, leading the cell to become cancerous, with the number of mutations constantly growing. So, when p53 remains intact, it is often able to prevent cancers from developing. When it suffers damage itself, cancers commonly result, explaining why p53 mutations are so frequently seen in so many different cancers.
“The presence of DNA breaks in precancerous and cancer cells may turn out to be the Achilles heel of cancer,” Dr. Halazonetis says. “It might be possible to inhibit repair of these DNA breaks, in which case the cancer cells would die.”
Almanac, Vol. 51, No. 29, April 19, 2005
April 19, 2005
Volume 51 Number 29