Researchers offer the first evidence that DNA damage can lead to the regulation of inflammatory responses, the body’s reaction to injury. The proteins involved in the regulation help protect the body from infection.

The study, performed by scientists at the National Institute of Environmental Health Sciences (NIEHS), which is part of the National Institutes of Health, is one of the first studies to come out of the recently established NIEHS Clinical Research Unit (CRU).

Appearing in the March 31 issue of PLoS Genetics, the research suggests that an injury to chromosomes alters the expression of a family of genes known as Toll-like receptors (TLRs). TLRs are proteins that play a role in the immune system by defending the body from infection. Following damage, the TLRs interact with the tumor suppressor gene p53 to regulate the amount of inflammation. The NIEHS investigators also establish that the integration of p53 and inflammation only occurs in primates.

Healthy volunteers with informed consent donated their blood cells for the study. The scientists separated white blood cells from the samples and exposed the cells to anti-cancer agents to activate p53. They then examined the expression of TLR genes. The team detected large variations among individuals, but found that p53 generally led to the activation of several TLR genes in patients’ cells. They also found that TLR activation could be prevented by adding the p53 inhibitor pifithrin.

“We would not have found this connection if we only worked with rat or mice cells,” said Michael Resnick, Ph.D., principal investigator in the Laboratory of Molecular Genetics (LMG) and corresponding author on the paper. “We needed to have human samples, so our collaboration with the CRU was crucial for these experiments.”

Stavros Garantziotis, M.D., a principal investigator in the Laboratory of Respiratory Biology (LRB) and the medical director for the CRU, is a co-author on the article. He said that the publication had two main findings: humans evolved an inflammatory response when subjected to DNA damage, and the variation in TLR activity among humans suggests that some people are more prone to inflammation following DNA damage, for example, after receiving cancer therapy.

“Physicians don’t have this information now, but understanding who would likely benefit from anti-inflammatory treatment after chemotherapy would greatly increase a doctor’s ability to help his or her patient in the future,” Garantziotis continued.

As a physician and co-author of the publication, LRB principal investigator Michael Fessler, M.D., went a step further in his explanation of how stimulating the human immune system could treat infection, and autoimmune and environmental diseases.

“The immune system very likely plays a role, not only in all inflammatory diseases that afflict humans, but also in cancer,” Fessler concluded. “Because of the new connection discussed in our paper, we may have a new means to manipulate the responses that affect those diseases.”

Now, the researchers are taking advantage of another NIEHS translational program, the Environmental Polymorphisms Registry (EPR), an ongoing study to collect DNA samples from nearly 20,000 North Carolinians. The EPR study will allow scientists to look for genes linked to disease. The study is a collaborative effort between NIEHS and the General Clinical Research Center at the University of North Carolina at Chapel Hill.

Daniel Menendez, Ph.D., and Maria Shatz, Ph.D., are two LMG scientists who share first authorship on the paper. Menendez added that the EPR work will permit researchers to further examine the association between p53 and inflammation. “In related studies, we are looking at individuals who have genetic alterations in the way they might respond to p53 activation,” he said. “We will try to determine if their cells behave differently, and if these subjects have changes in their inflammatory response, or an increased risk for certain inflammatory diseases.”

Reference:
Menendez D*, Shatz M*, Azzam K, Garantziotis S, Fessler MB, Resnick MA. 2011. The Toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet [Online 31 March 2011]. (*co-first authors)

• NIH/National Institute of Environmental Health Sciences
• PLoS Genetics

In response to the ongoing situation in Japan, the U.S. Environmental Protection Agency (EPA) has taken steps to increase the level of nationwide monitoring of milk, precipitation, drinking water, and other potential exposure routes.

EPA conducts radiological monitoring of milk under its RADNET program, while the U.S. Food and Drug Administration has jurisdiction over the safety, labeling and identity of milk and milk products in interstate commerce. States have jurisdiction over those facilities located within their territory.

Results from a screening sample taken March 25 from Spokane, Wash. detected 0.8 pCi/L of iodine-131, which is more than 5,000 times lower than the Derived Intervention Level set by the U.S. Food and Drug Administration. These types of findings are to be expected in the coming days and are far below levels of public health concern, including for infants and children. Iodine-131 has a very short half-life of approximately eight days, and the level detected in milk and milk products is therefore expected to drop relatively quickly.

“Radiation is all around us in our daily lives, and these findings are a minuscule amount compared to what people experience every day. For example, a person would be exposed to low levels of radiation on a round trip cross country flight, watching television, and even from construction materials,” said Patricia Hansen, an FDA senior scientist.

EPA’s recommendation to state and local governments is to continue to coordinate closely with EPA, FDA and CDC. EPA will continue to communicate our nationwide sampling results as they come in.

Additional information on EPA’s accelerated drinking water and precipitation sampling

Daily Data Summary

RadNet Air Monitoring Data

• Daily Data Summary
• EPA’s RadNet Air Monitoring Data
  • Air Filter and Cartridge Results
• Frequently Asked Questions
  • Preguntas más frecuentes

Questions about Medical Products

Hypothetically, if they were needed, what are the FDA-approved products for treatment of internal contamination with radioactive iodine?

There are three FDA-approved potassium iodide (KI) products for use as an adjunct to other public health protective measures in the event that radioactive iodine is released into the environment. The three over-the-counter products are:

• Iosat Tablets (130 mg), Anbex, Inc., Williamsburg, Va., http://www.anbex.com
• ThyroSafe Tablets (65 mg), Recipharm AB, Jordbro, Sweden, http://www.thyrosafe.com
• ThyroShield Solution (65 mg/mL), Fleming & Company Pharmaceuticals, Fenton, Mo.http://www.thyroshield.com

When administered at the recommended dose, KI is effective in reducing the risk of thyroid cancer in people at risk for inhalation or ingestion of radioactive iodine. KI floods the thyroid with non-radioactive iodine and prevents the uptake of the radioactive molecules. Potassium iodide works only to prevent the thyroid from uptaking radioactive iodine. It is not a general radioprotective agent.

Potassium Iodide (KI)

• Frequently Asked Questions on Potassium Iodide (KI) (2/21/2002; updated 3/29/2011)
• Potassium Iodide (KI) Information (Centers for Disease Control and Prevention)
• Guidance: Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies (PDF – 40KB) (12/2001)
  Guidance on using potassium iodide to reduce the risk of thyroid cancer in children and adults in emergencies involving the release of radioactive iodine into the environment
• FDA Talk Paper: Guidance on Protection of Children and Adults Against Thyroid Cancer in Case of Nuclear Accident (12/10/2001)
• Guidance for Federal Agencies and State and Local Governments: Potassium Iodide Tablets: Shelf Life Extension (PDF – 156KB) (3/2004)
• Home Preparation Procedure for Emergency Administration of Potassium Iodide Tablets to Infants and Small Children(PDF – 33KB) (7/3/2002)
  • • Easy-to-use, one-page instructions for home preparation of 130 mg tablets(PDF – 329KB) (10/22/2002)
    • Easy-to-use, one-page instructions for home preparation of 65 mg tablets(PDF – 331KB) (10/22/2002)
• Guidance for Industry: KI in Radiation Emergencies-Questions and Answers (PDF – 161KB) (12/20/2002)
• The Risk of Severe Allergic Reactions from the Use of Potassium Iodide for Radiation Emergencies
  Position statement from the American Academy of Allergy, Asthma, and Immunology (8/16/2004

Is potassium iodide the only medication available for radiation exposure?

Potassium iodide is the only FDA-approved medication available to treat contamination with radioactive iodine. There are FDA-approved products available that increase the rate of elimination of other radioactive elements. They include:

• Calcium-DTPA and Zinc DTPA, Hameln Pharmaceuticals. Approved to treat known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination.

• Radiogardase (Prussian blue insoluble capsules), HEYL Chemisch-Pharmazeutische Fabrik GmbH & Co. KG. Approved to treat known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase their rates of elimination.

Calcium-DTPA and Zinc-DTPA
Conditions under which calcium-DTPA (Ca-DTPA) and zinc-DTPA (Zn-DTPA) can be found to be safe and effective for the treatment of internal contamination with plutonium, americium, or curium to increase the rates of elimination of these substances from the body (9/12/2003)

Prussian Blue Information
FDA approved Radiogardase, also known as Prussian blue, to treat people exposed to radiation contamination due to harmful levels of cesium-137 or thallium. (10/2/2003)

• Radiogardase (Prussian Blue) Labeling (PDF – 208KB) (prescribing information for children and adults)
• FDA approves the first New Drug Application for treatment of radiation contamination. FDA News (Posted 10/2/2003)
• Label for Radiogardase (8/2008)
• Questions and Answers on Prussian Blue (Updated 10/2/2003)
• FDA encourages manufacturers to submit marketing applications for Prussian Blue. FDA Press Release (1/31/2003)
• Guidance for Industry on Prussian Blue for Treatment of Internal Contamination with Thallium or Radioactive Cesium; Availability (Optional version: PDF – 49KB)
• Guidance for Industry: Prussian Blue Drug Products–Submitting a New Drugs Applications (PDF – 178KB)

Guidance Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies

Click here for the guidance that represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutesand regulations.

The objective of this document is to provide guidance to other Federal agencies, including the Environmental Protection Agency (EPA) and the Nuclear Regulatory Commission (NRC), and to state and local governments regarding the safe and effective use of potassium iodide (KI) as an adjunct to other public health protective measures in the event that radioactive iodine is releasedinto the environment.

The adoption and implementation of these recommendations are at the discretion of the state and local governments responsible for developing regional emergency response plans related to radiation emergencies.This guidance updates the Food and Drug Administration (FDA) 1982 recommendations for the use of KI to reduce the risk of thyroid cancer in radiation emergencies involving the release ofradioactive iodine.  The recommendations in this guidance address KI dosage and the projected radiation exposure at which the drug should be used.

These recommendations were prepared by the Potassium Iodide Working Group, comprisingscientists from the FDA’s Center for Drug Evaluation and Research (CDER) and Center forDevices and Radiological Health (CDRH) in collaboration with experts in the field from theNational Institutes of Health (NIH).  Although they differ in two respects (as discussed inSection IV.B), these revised recommendations are in general accordance with those of the WorldHealth Organization (WHO), as expressed in its Guidelines for Iodine Prophylaxis FollowingNuclear Accidents: Update 1999 (WHO 1999).

New research in the FASEB Journal suggests that the absence of intestinal toll-like receptor 2 affects , pointing to a new way to manage weight and intestinal problems

If you are looking to lose weight in the coming year, you may need help from an unexpected place: the bacteria in your gut. That’s because scientists have discovered that the bacteria living in your intestines may play a far more significant role in weight loss and gastrointestinal problems than ever imagined. In a new research report published  in The FASEB Journal, researchers show that a deficiency of Toll-like receptor 2 (Tlr2)—used by mammals (including humans) to recognize resident microbes in the intestines—leads to changes in gut bacteria that resemble those of lean animals and humans. This discovery builds on previous research demonstrating that a deficiency of TLR2 protects against obesity, while at the same time promoting gastrointestinal problems like excessive inflammation. It also shows that genes controlling TLR2 expression play a very important role in one’s gastrointestinal health and weight management.

“Our work highlights the remarkable capacity for an orchestrated reprogramming of the intestinal inflammatory network to overcome significant genetic challenges in the mammalian bowel,” said Richard Kellermayer, Ph.D., a researcher involved in the work from the Section of Pediatric Gastroenterology, Hepatology and Nutrition at Baylor College of Medicine in Houston. “The appropriate exploitation of this remarkable capacity may provide means for the prevention and optimized treatment of common metabolic (such as obesity and diabetes) and gastrointestinal disorders.”

To make this discovery, Kellermayer and colleagues studied normal mice and mice deficient in TLR2 using the large intestinal lining of these mice. They compared the TLR2-deficient ones to the normal group, as well as the bacteria, the epigenome (more specifically DNA methylation, a molecular change in the DNA associated with decreased gene expression), and the gene expression of the animals. The researchers found that the absence of TLR2 leads to microbial changes in the gut that resemble lean animals and humans, as well as immunologic changes similar to those observed in ulcerative colitis.

“Every New Year, a significant percentage of us resolve ourselves to lose weight,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal, “but national statistics on obesity show that we’re failing fast. This research linking gut bacteria to TLR2 expression opens entirely new doors for weight control solutions, first by cementing TLR2 as a drug target for obesity, and second by providing further evidence that managing gut bacteria may be an important and effective way to control weight. The challenge, of course, is to find a way to tip the scales just enough to keep weight under control without causing serious gastrointestinal problems.”

Research more on the net:

• Federation of American Societies for Experimental Biology
• FASEB Journal

Three basic concepts apply to all types of ionizing radiation. When we develop regulations or standards that limit how much radiation a person can receive in a particular situation, we consider how these concepts might affect a person’s exposure.

The 3 Basic Concepts of Radiation Protection revolve around: time, distance, shielding

Time
The amount of radiation exposure increases and decreases with the time people spend near the source of radiation.

In general, we think of the exposure time as how long a person is near radioactive material. It’s easy to understand how to minimize the time for external (direct) exposure. Gamma and x-rays are the primary concern for external exposure.

However, if radioactive material gets inside your body, you can’t move away from it. You have to wait until it decays or until your body can eliminate it. When this happens, the biological half-life of the radionuclide controls the time of exposure. Biological half-life is the amount of time it takes the body to eliminate one half of the radionuclide initially present. Alpha and beta particles are the main concern for internal exposure.

How does EPA use the concept of time in radiation protection?

When we set a radiation standard that assumes an exposure over a certain period, we are applying the concept of time. For example, we often express exposures in terms of a committed dose. A committed dose is one that accounts for continuing exposures over long periods of time (such as 30, 50, or 70 years). It refers to the exposure received from radioactive material that enters and remains in the body for many years.

When we assess the potential for exposure in a situation, we consider the amount of time a person is likely to spend in the area of contamination. For example, in assessing the potential exposure from radon in a home, we estimate how much time people are likely to spend in the basement.

Distance
The farther away people are from a radiation source, the less their exposure.

How close to a source of radiation can you be without getting a high exposure? It depends on the energy of the radiation and the size (or activity) of the source. Distance is a prime concern when dealing with gamma rays, because they can travel long distances. Alpha and beta particles don’t have enough energy to travel very far.

As a rule, if you double the distance, you reduce the exposure by a factor of four. Halving the distance, increases the exposure by a factor of four.

Why does exposure change more rapidly than the distance?

The area of the circle depends on the distance from the center to the edge of the circle (radius). It is proportional to the square of the radius. As a result, if the radius doubles, the area increases four times.

Think of the radiation source as a bare light bulb. The bulb gives off light equally in every direction, in a circle. The energy from the light is distributed evenly over the whole area of the circle. When the radius doubles, the radiation is spread out over four times as much area, so the dose is only one fourth as much. (In addition, as the distance from the source increases so does the likelihood that some gamma rays will lose their energy.

The exposure of an individual sitting 4 feet from a radiation source will be 1/4 the exposure of an individual sitting 2 feet from the same source

How does EPA use the concept of distance in radiation protection?

We also consider distance in analyzing potential exposures from a source. If a person is at a contaminated site, or working around radioactive material, we assess how the exposures vary if the person is closer to, or farther away from, the source of radiation.

Shielding
The greater the shielding around a radiation source, the smaller the exposure.

Shielding simply means having something that will absorb radiation between you and the source of the radiation (but using another person to absorb the radiation doesn’t count as shielding). The amount of shielding required to protect against different kinds of radiation depends on how much energy they have.

(Alpha)
A thin piece of light material, such as paper, or even the dead cells in the outer layer of human skin provides adequate shielding because alpha particles can’t penetrate it. However, living tissue inside body, offers no protection against inhaled or ingested alpha emitters.

(Beta)
Additional covering, for example heavy clothing, is necessary to protect against beta-emitters. Some beta particles can penetrate and burn the skin.

(Gamma)
Thick, dense shielding, such as lead, is necessary to protect against gamma rays. The higher the energy of the gamma ray, the thicker the lead must be. X-rays pose a similar challenge, so x-ray technicians often give patients receiving medical or dental X-rays a lead apron to cover other parts of their body.

How does EPA use the concept of shielding in radiation protection?

We take into account the type of shielding that might be provided by soil when we assess sites that have been contaminated or used for disposal of radioactive material. We also account for the shielding provided by buildings for a person working or living at a site that has been cleaned up.

What kinds of health effects does exposure to radiation cause?

In general, the amount and duration of radiation exposure affects the severity or type of health effect. There are two broad categories of health effects: stochastic and non-stochastic.

Stochastic Health Effects

Stochastic effects are associated with long-term, low-level (chronic) exposure to radiation. (“Stochastic” refers to the likelihood that something will happen.) Increased levels of exposure make these health effects more likely to occur, but do not influence the type or severity of the effect.

Cancer is considered by most people the primary health effect from radiation exposure. Simply put, cancer is the uncontrolled growth of cells. Ordinarily, natural processes control the rate at which cells grow and replace themselves. They also control the body’s processes for repairing or replacing damaged tissue. Damage occurring at the cellular or molecular level, can disrupt the control processes, permitting the uncontrolled growth of cells–cancer. This is why ionizing radiation’s ability to break chemical bonds in atoms and molecules makes it such a potent carcinogen.

Other stochastic effects also occur. Radiation can cause changes in DNA, the “blueprints” that ensure cell repair and replacement produces a perfect copy of the original cell. Changes in DNA are called mutations.

Sometimes the body fails to repair these mutations or even creates mutations during repair. The mutations can be teratogenic or genetic. Teratogenic mutations are caused by exposure of the fetus in the uterus and affect only the individual who was exposed. Genetic mutations are passed on to offspring.

Non-Stochastic Health Effects

Non-stochastic effects appear in cases of exposure to high levels of radiation, and become more severe as the exposure increases. Short-term, high-level exposure is referred to as ‘acute’ exposure.

Many non-cancerous health effects of radiation are non-stochastic. Unlike cancer, health effects from ‘acute’ exposure to radiation usually appear quickly. Acute health effects include burns and radiation sickness. Radiation sickness is also called ‘radiation poisoning.’ It can cause premature aging or even death. If the dose is fatal, death usually occurs within two months. The symptoms of radiation sickness include: nausea, weakness, hair loss, skin burns or diminished organ function.

Medical patients receiving radiation treatments often experience acute effects, because they are receiving relatively high “bursts” of radiation during treatment.

After a good night’s sleep, people remember information better when they know it will be useful in the future, according to a new study in the Feb. 2 issue of The Journal of Neuroscience. The findings suggest that the brain evaluates memories during sleep and preferentially retains the ones that are most relevant.

Humans take in large amounts of information every day. Most is encoded into memories by the brain and initially stored, but the majority of information is quickly forgotten. In this study, a team of researchers led by Jan Born, PhD, of the University of Lübeck in Germany set out to determine how the brain decides what to keep and what to forget.

“Our results show that memory consolidation during sleep indeed involves a basic selection process that determines which of the many pieces of the day’s information is sent to long-term storage,” Born said. “Our findings also indicate that information relevant for future demands is selected foremost for storage.”

The researchers set up two experiments to test memory retrieval in a total of 191 volunteers. In the first experiment, people were asked to learn 40 pairs of words. Participants in the second experiment played a card game where they matched pictures of animals and objects — similar to the game Concentration — and also practiced sequences of finger taps.

In both groups, half the volunteers were told immediately following the tasks that they would be tested in 10 hours. In fact, all participants were later tested on how well they recalled their tasks.

Some, but not all, of the volunteers were allowed to sleep between the time they learned the tasks and the tests. As the authors expected, the people who slept performed better than those who didn’t. But more importantly, only the people who slept and knew a test was coming had substantially improved memory recall.

The researchers also recorded electroencephalograms (EEG) from the individuals who were allowed to sleep. They found an increase in brain activity during deep or “slow wave” sleep when the volunteers knew they would be tested for memory recall.

“The more slow wave activity the sleeping participants had, the better their memory was during the recall test 10 hours later,” Born said. Scientists have long thought that sleep is important in memory consolidation. The authors suggest that the brain’s prefrontal cortex “tags” memories deemed relevant while awake and the hippocampus consolidates these memories during sleep.

Gilles Einstein, PhD, an expert in memory at Furman University, said the new findings help explain why you are more likely to remember a conversation about impending road construction than chitchat about yesterday’s weather. “These results suggest that sleep is critical to this memory enhancement,” said Einstein, who was unaffiliated with the study. “This benefit extends to both declarative memories (memory for a road detour) and procedural memories (memory for a new dance step).”

The research was supported by the German Research Foundation.

———————————————————————————————-

Article adapted by MD Only from original press release.

———————————————————————————————-

Provided by Society for Neuroscience

If you see a student dozing in the library or a co-worker catching 40 winks in her cubicle, don’t roll your eyes. New research from the University of California, Berkeley, shows that an hour’s nap can dramatically boost and restore your brain power. Indeed, the findings suggest that a biphasic sleep schedule not only refreshes the mind, but can make you smarter.

Conversely, the more hours we spend awake, the more sluggish our minds become, according to the findings. The results support previous data from the same research team that pulling an all-nighter — a common practice at college during midterms and finals — decreases the ability to cram in new facts by nearly 40 percent, due to a shutdown of brain regions during sleep deprivation.

“Sleep not only rights the wrong of prolonged wakefulness but, at a neurocognitive level, it moves you beyond where you were before you took a nap,” said Matthew Walker, an assistant professor of psychology at UC Berkeley and the lead investigator of these studies.

In the recent UC Berkeley sleep study, 39 healthy young adults were divided into two groups — nap and no-nap. At noon, all the participants were subjected to a rigorous learning task intended to tax the hippocampus, a region of the brain that helps store fact-based memories. Both groups performed at comparable levels.

Students who napped (green column) did markedly better in memorizing tests than their no-nap counterparts. Matthew Walker, assistant psychology professor, image above shows how that a nap clears the brain to absorb new information.

In the recent UC Berkeley sleep study, 39 healthy young adults were divided into two groups — nap and no-nap. At noon, all the participants were subjected to a rigorous learning task intended to tax the hippocampus, a region of the brain that helps store fact-based memories. Both groups performed at comparable levels.

At 2 p.m., the nap group took a 90-minute siesta while the no-nap group stayed awake. Later that day, at 6 p.m., participants performed a new round of learning exercises. Those who remained awake throughout the day became worse at learning. In contrast, those who napped did markedly better and actually improved in their capacity to learn

These findings reinforce the researchers’ hypothesis that sleep is needed to clear the brain’s short-term memory storage and make room for new information, said Walker, who presented his preliminary findings on Sunday, Feb. 21, at the annual meeting of the American Association of the Advancement of Science (AAAS) in San Diego, Calif.

Since 2007, Walker and other sleep researchers have established that fact-based memories are temporarily stored in the hippocampus before being sent to the brain’s prefrontal cortex, which may have more storage space.

“It’s as though the e-mail inbox in your hippocampus is full and, until you sleep and clear out those fact e-mails, you’re not going to receive any more mail. It’s just going to bounce until you sleep and move it into another folder,” Walker said.

In the latest study, Walker and his team have broken new ground in discovering that this memory-refreshing process occurs when nappers are engaged in a specific stage of sleep. Electroencephalogram tests, which measure electrical activity in the brain, indicated that this refreshing of memory capacity is related to Stage 2 non-REM sleep, which takes place between deep sleep (non-REM) and the dream state known as Rapid Eye Movement (REM). Previously, the purpose of this stage was unclear, but the new results offer evidence as to why humans spend at least half their sleeping hours in Stage 2, non-REM, Walker said.

“I can’t imagine Mother Nature would have us spend 50 percent of the night going from one sleep stage to another for no reason,” Walker said. “Sleep is sophisticated. It acts locally to give us what we need.”

Walker and his team will go on to investigate whether the reduction of sleep experienced by people as they get older is related to the documented decrease in our ability to learn as we age. Finding that link may be helpful in understanding such neurodegenerative conditions as Alzheimer’s disease, Walker said.

In addition to Walker, co-investigators of these new findings are UC Berkeley post-doctoral fellow Bryce A. Mander and psychology undergraduate Sangeetha Santhanam.

———————————————————————-

Article adapted by MD Only from original press release.

———————————————————————-

Contact: Yasmin Anwar
University of California, Berkley

In a study published in the Journal of Clinical Investigation, a team led by Virginia M.-Y. Lee, PhD, director of Penn’s Center for Neurodegenerative Disease Research, describes the first direct evidence of how mutated TDP-43 can cause neurons to die. Although normally found in the nucleus where it regulates gene expression, TDP-43 was first discovered in 2006 to be the major disease protein in ALS and FTLD by the Penn team led by Lee andJohn Q. Trojanowski, MD, PhD, director of the Institute on Aging at Penn. This discovery has transformed research on ALS and FTLD by linking them to the same disease protein.

Caption: Top panels show progenitor cells marked in green (left) and brown (right) in cross section of a hair follicle. Bottom panel shows side view of hair follicle with stem-cell- and progenitor-cell-rich areas.

Credit: George Cotsarelis, MD, University of Pennsylvania School of Medicine

“The discovery of TDP-43 as the pathological link between mechanisms of nervous system degeneration in both ALS and FTLD opened up new opportunities for drug discovery as well as biomarker development for these disorders,” says Lee. “An animal model of TDP-43-mediated disease similar to ALS and FTLD will accelerate these efforts.”

In the case of TDP-43, neurons could die for two reasons: One, the clumps themselves are toxic to neurons or, two, when TDP-43 is bound up in clumps outside the nucleus, it depletes the cell of normally functioning TDP-43. Normally a cell regulates the exact amount of TDP-43 in itself — too much is bad and too little is also bad. The loss of function of TDP-43 is important in regulating disease because it regulates gene expression.

To determine the effects of misplaced TDP-43 on the viability of neurons, the researchers made transgenic mice expressing human mutated TDP-43 in the cytoplasm and compared them to mice expressing normal human TDP-43 in the nucleus of nerve cells. Expression of either human TDP-43 led to neuron loss in vulnerable forebrain regions; degeneration of part of the spinal cord tract; and muscle spasms in the mice. These effects recapitulate key aspects of FTLD and a subtype of ALS known as primary lateral sclerosis.

The JCI study showed that a dramatic loss of function causes nerve-cell death because normal mouse TDP-43 is eliminated when human mutated TDP-43 genes are put into the mice. Since cells regulate the exact amount of TDP-43, over-expression of the human TDP-43 protein prevents the mouse TDP-43 from functioning normally. Lee and colleagues think this effect leads to neuron death rather than clumps of TDP-43 because these clumps were rare in the mouse cells observed in this study. Lee says that it is not yet clear why clumps were rare in this mouse model when they are so prevalent in human post-mortem brain tissue of ALS and FTLD patients.

Neurodegeneration in the mouse neurons expressing TDP-43 — both the normal and mutated human versions — was accompanied by a dramatic downregulation of the TDP-43 protein mice are born with. What’s more, mice expressing the mutated human TDP-43 exhibited profound changes in gene expression in neurons of the brain’s cortex.

The findings suggest that disturbing the normal TDP-43 in the cell nucleus results in loss of normal TDP-43 function and gene regulatory pathways, culminating in degeneration of affected neurons.

Next steps, say the researchers, will be to look for the specific genes that are regulated by TDP-43 and how mRNA splicing is involved so that the abnormal regulation of these genes can be corrected.

At the same time, notes Lee, “We soon will launch studies of novel strategies to prevent TDP-43-mediated nervous system degeneration using this mouse model of ALS and FTLD.”

The study was funded in part by funds from the National Institutes of Health.

———————————————————————-

Article adapted by MD Only from original press release.

———————————————————————-

Contact: Karen Kreeger
University of Pennsylvania School of Medicine