Posted on: Wednesday, 9 March 2011, 13:42 CST

Medication turns on critical gene, protects brain cells

In a major breakthrough in the battle against Parkinson’s disease, researchers at the University of Colorado School of Medicine have discovered a drug that stops the progression of the degenerative illness in mice and is now being tested in humans.

"Drugs currently used to treat Parkinson’s disease just treat symptoms; they do not stop the disease from getting worse," said senior author Curt Freed, MD, who heads the division of Clinical Pharmacology and Toxicology at the CU School of Medicine. "We’ve now discovered that we can prevent the progression of the disease by turning on a protective gene in the brain."

The results have been published on line in the Journal of Biological Chemistry, jbc.org/content/early/2011/03/03/jbc.M110.211029.full.pdf+html.

Lead author Wenbo Zhou, PhD, Assistant Professor of Medicine, and Freed, a national pioneer in Parkinson’s research, have found that the drug phenylbutyrate turns on a gene that can protect dopamine neurons in Parkinson’s disease. The gene, called DJ-1, can increase production of antioxidants like glutathione to reduce the debilitating effects of excess oxygen in brain cells. In addition, activating DJ-1 helps cells eliminate abnormal proteins that otherwise accumulate and kill brain cells. Dopamine neurons are particularly susceptible to too much oxygen and abnormal protein deposits. Parkinson’s disease is caused by dying midbrain dopamine neurons.

Zhou and Freed have studied the DJ-1 gene since 2003 when a European group discovered that mutations in DJ-1 could cause Parkinson’s disease. The Colorado scientists immediately started work to see why the gene was so important and have published a series of papers on the subject since 2005. but to convert their findings into a practical treatment for Parkinson’s disease, they needed to find a drug to turn on the DJ-1 gene.

"we know some drugs can turn on genes. for example, steroids like testosterone act on genes in muscle cells to create muscle bulk," said Freed.

After testing many drugs, the team found that phenylbutyrate could activate DJ-1 and keep dopamine neurons from dying. next, they put the drug in the drinking water of mice genetically programmed to get Parkinson’s disease as they aged.

Aging mice receiving the drug were able to move normally, had no decline in mental function, and their brains did not accumulate the protein that causes Parkinson’s. By contrast, older animals that did not get the drug saw a steady decline in their ability to move as their brains were damaged by abnormal proteins.

The researchers began giving phenylbutyrate to people in 2009, to test the safety of the drug in Parkinson patients.

Zhou and Freed will publish the human results in the coming months.

"we look forward to a future when Parkinson patients will be able to take a pill that will turn on the DJ-1 gene and stop the progressive disability associated with the illness," Freed said. "Right now, when you get the diagnosis of Parkinson’s, you can expect to have a steady decline in the ability to move. While drugs like L-DOPA are very important for generating dopamine in the brain and making movement possible, these drugs have little impact on the ongoing deterioration of the patients’ own brain cells."

Over one million people in the United State have the disease which usually strikes those in their 50s and 60s. Patients have a decline in their ability to walk, talk, and write because of slow movement and rigid muscles. They develop tremors and reflexes slow down. The current treatment of Parkinson’s is based on drugs that increase dopamine production in the brain.

Freed is a national leader in transplanting dopamine cells into the human brain to relieve symptoms. He and his neurosurgical colleague Robert Breeze, MD, have done the operation in 61 patients, more than any other group in the world. The procedure can replace the need for drugs but even cell transplants do not prevent the progression of the disease.

Freed and Zhou are now looking for other drugs that might turn on the DJ-1 gene. One drawback of phenylbutyrate is that patients must take very large doses, 16 grams per day or 32 large tablets taken at frequent intervals. While the drug is approved by the FDA for treating a rare genetic disease in infants, whether it can stop Parkinson’s in people remains to be seen.

But Zhou and Freed believe the discovery offers new hope for those suffering from Parkinson’s disease.

"if we can say to someone that as of today we can stop your disease from getting worse, that would be a truly significant achievement," Freed said.

• University of Colorado Denver
• Journal of Biological Chemistry

More News in this Category

Published on Mon Jan 17 09:20:59 GMT 2011

“A new technique could lead to a blood test for detecting Alzheimer’s,” BBC News reported.

This news story is based on research that has developed a new method to screen blood for antibodies, a range of proteins that the body creates in response to specific diseases. The technique involved passing blood samples over special slides coated with a synthetic substance designed to identify antibodies found only in people with a specific disease. Researchers first refined the test in mice and then focused on Alzheimer’s disease in humans. They found that there were raised levels of two antibodies in the blood of 16 people with Alzheimer’s disease but not in 14 unaffected people.

This promising technique may eventually lead to blood tests for conditions such as Alzheimer’s disease. however, this research is in its early stages and now needs testing in much larger groups of people to confirm that these two antibodies are actual markers of Alzheimer’s. Additionally, the study did not determine at what point in the disease levels of these antibodies become raised, so we cannot presently tell if it can detect early-stage Alzheimer’s disease.

The study was carried out by researchers from the Scripps Research institute in Florida and was funded by the US National Institutes of Health. it was published in Cell, a peer-reviewed scientific journal.

This research was generally covered adequately by the media, with most newspapers highlighting the preliminary nature of the research. however, as yet, the researchers have not determined how early in the course of Alzheimer’s disease the antibody changes could be detected. at present, it is not possible to say whether this test would be able to detect Alzheimer’s disease any earlier than current diagnostic tests, as some newspapers have prematurely suggested.

When the body mounts an immune response to disease or infection, it may produce antibodies. These are specific proteins that help the body neutralise the threat it has encountered. Once antibodies are created to deal with a specific illness or substance, the body can easily reproduce them if exposed again. This is why previously having an illness or receiving a vaccination can provide increased immunity. Substances that cause us to produce antibodies are called antigens, and can include proteins, foreign cells and bacteria.

This laboratory study developed a potential method to screen for the immune response to various diseases using slides covered in special synthetic chemicals, which would show the presence of antibodies consistent with specific diseases. The technique was then tested to determine whether it could find a difference in the antibodies produced by people with Alzheimer’s disease and by healthy control subjects. usually, diagnosis of Alzheimer’s disease requires a series of cognitive tests and the exclusion of other causes through brain imaging. it can only be confirmed by looking at changes in the brain after death.

To find antibodies that may be relevant to diseases, researchers currently use libraries of antigens. By passing blood over these, they can detect whether an individual has relevant antibodies as these will bind to the appropriate antigen. however, when screening for new antibodies that may be produced in a particular disease, this approach is not especially useful as the antigens being screened for are selected based on the likelihood that they play a role in the disease. Additionally, some proteins involved in different diseases are normally produced by the body, meaning the body would not have produced any antibodies against them. however, if normal proteins undergo changes to become the “disease form” of the protein, this may trigger an immune response.

To search for antibodies, the researchers used unnatural synthetic molecules called “peptoids”. These peptoids can form shapes that cannot be made by normal unmodified proteins but may mimic some aspects of the shape of disease proteins, allowing them to bind to antibodies specifically created in response to certain diseases.

The researchers made 4,608 synthetic peptoids of varying shapes and fixed their position on microscope slides. They then took blood from a mouse that had been treated with chemicals to make it develop symptoms resembling multiple sclerosis (MS). MS affects the nervous system, in which an immune response is thought to contribute to the disease’s progression.

The blood was passed over the microscope slide so that the antibodies in the blood could bind to the peptoids. The researchers then used a secondary antibody, which would bind to any mouse antibodies that had bound to the various peptoids on the slide. The secondary antibody was fluorescent so it could be visually detected.

The researchers used this initial experiment to optimise the concentration of blood and to find some peptoids that had bound antibodies. They then used the slides to compare blood from the mice with MS to blood from normal, control mice. if there were areas on the slide where bonding had occurred using MS mouse blood but not control mouse blood, it might indicate antibodies that were specifically produced in response to the MS-like condition.

The researchers then continued their experiments in humans, looking at whether they could see a difference between blood samples from people with Alzheimer’s disease and those of healthy elderly people. They took stored blood samples from six people with Alzheimer’s disease (three of whom had had their Alzheimer’s confirmed following autopsy) and six age-matched, healthy controls. The researchers passed the blood samples over a slide containing 15,000 peptoids. To make sure that any result was specific for Alzheimer’s disease, they also analysed six samples from people with Parkinson’s disease.

After using the screening technique to initially to find peptoids that bound antibodies from people with Alzheimer’s but not controls, the researchers repeated the test in an additional 16 Alzheimer’s samples, 14 controls and six people with lupus (an immune disease).

In the mouse model of MS, the researchers found that an antibody binding to three peptoids, which they named AMogP1-3, could differentiate between healthy mice and mice with MS-like symptoms. They were able to determine that the antibody that bound to the AMogP1-3 peptoids was the antibody that bound to a protein called Mog. Injection with the Mog protein had been used to cause MS symptoms in the mice. This was a proof of concept that use of an unnatural molecule could confirm the presence of an antibody that recognises a disease-triggering protein.

For the Alzheimer’s screening, the researchers chose three spots on the slide which had the greatest fluorescent signal (indicating that lots of antibodies had bound). These sites contained three peptoids that distinguished the people with Alzheimer’s from the controls. The researchers named the peptoids AD peptoids (ADP) 1-3. at least three times as many antibodies had bound in the Alzheimer’s samples compared to the control samples.

In the larger sample of Alzheimer’s and controls, the researchers found that the sensitivity (percentage of Alzheimer’s samples correctly identified as having Alzheimer’s) was 93.7% and the specificity (percentage of control samples correctly identified as control samples) was between 93.7% and 100% for each of the peptoids.

They found that ADP1 and ADP3 bound to the same antibody, while ADP2 bound to a different antibody.

The researchers said that their new approach did not require them to identify a specific antigen to screen for antibodies that are raised in disease. rather, by using a large collection of unnatural molecules, some of which may happen to have the right shape to bind to an antibody, they were able to carry out a high level of screening in samples of people with disease compared to controls.

They said that for Alzheimer’s samples, their “preliminary study is promising as it represents a high level of diagnostic sensitivity and specificity, at least within the relatively limited range of samples analyzed”. However, they pointed out that “more work will be required before it is clear whether the peptoids ADP1-3 will be useful for the clinical diagnosis of Alzheimer’s disease”.

This research has applied a novel approach to antibody screening, using slides coated with thousands of synthetic molecules to screen blood samples for antibodies associated with specific diseases. This well-conducted preliminary research may potentially provide a new method to screen for the presence antibodies that may be characteristic of a disease, and may also aid diagnostics.

When tested in a small number of blood samples from people with Alzheimer’s disease and healthy controls, the researchers’ method could clearly discriminate between the two groups and found higher levels of two antibodies in the Alzheimer’s samples compared to the controls.

While this interesting work could theoretically screen for a range of conditions, the researchers rightly highlight the preliminary nature of their study and emphasise that more work is needed before this could be a diagnostic test for Alzheimer’s or any other disease. In particular, they say:

• There is now the need for analysis of samples from a larger number of patients from a more diverse population.
• The samples came from people who had a confirmed diagnosis of Alzheimer’s disease. it is important to test samples from patients who have milder cognitive impairment that subsequently progresses to Alzheimer’s disease to see whether it is possible to use this test for early detection of Alzheimer’s disease.
• While the test can identify the presence of antibodies consistent with a particular disease, it cannot identify which antigens the antibody is designed to neutralise. Therefore, the technique cannot determine which proteins may cause or contribute to the development of a disease.

Overall, this is promising research that may lead to a blood test for Alzheimer’s and other diseases, although it is still at an early stage. To progress, the technique will need further validation in much larger groups of people.

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Study Shows Demanding Relationship With a Partner May have an Impact on Heart Health

Dec. 23, 2010 — just in time for those holiday family gatherings comes news that family stress — especially stress involving spouses and children — may hurt the heart.

People in a Danish study who reported having a worrisome or demanding relationship with a partner had a more than threefold increased risk for developing the severe chest pain condition known as angina.

Angina is both a warning sign and symptom of heart disease.

Researchers followed more than 4,500 men and women in their 40s and 50s with no known heart problems for six years. Those with the most stressful close family relationships had the highest risk of developing angina.

Study researcher Rikke Lund, MD, PhD, says it has long been known that positive social relationships are good for the heart. “We wanted to look at it another way and examine the impact of difficult social relationships on cardiovascular risk,” she tells WebMD.

Family Stress and the Heart

The randomly selected study participants were followed from 1999 to 2006, when they were asked about both their heart health and the quality of their relationships with the people in their lives, including partners, children, other relatives, friends, and neighbors.

Participants were specifically asked about the level of demand placed on them by family members and friends, the degree of worry associated with each relationship, and the degree and frequency of conflict.

During the six years of follow-up, roughly one in 10 study participants developed chest pains associated with angina.

Not surprisingly, older participants were more likely to report the condition than younger ones.

Having a worrisome or demanding relationship with a spouse or partner was associated with a more than 3.5-fold increase in angina risk, while a similar relationship with a child was associated with a twofold increase in risk.

The association was not quite as strong for other family members, and the impact of worries and demands involving non-family members was negligible.

Surprisingly, conflict with family members was much less strongly linked to angina risk than being in a worrisome or demanding relationship. People who reported having frequent arguments with a partner had a 44% increase in angina risk.

Second Opinion

Psychologist William R. Lovallo, PhD, who wrote the 2004 book Stress and Health: Biological and Psychological Interactions, says the study provides more evidence linking social relationships with health.

But he adds that it is not clear if the quality of these relationships has a direct impact on conditions like angina.

Lovallo is with the Veterans Affairs Medical Center in Oklahoma City and the department of psychiatry and behavioral sciences at the University of Oklahoma Health Science Center.

“It is tempting to assume that bad social relationships cause medical symptoms, but we have to be careful about making this association,” he tells WebMD.