Posts tagged neurodegeneration

Scientists at Rutgers and Emory universities have discovered that a compound often emitted by mold may be linked to symptoms of Parkinson’s disease.

Arati Inamdar and Joan Bennett, researchers in the School of Environmental and Biological Sciences at Rutgers, used fruit flies to establish the connection between the compound  – popularly known as mushroom alcohol – and the malfunction of two genes involved in the packaging and transport of dopamine, the chemical released by nerve cells to send messages to other nerve cells in the brain.

The findings were published online today in the Proceedings of the National Academy of Sciences.

“Parkinson’s has been linked to exposure to environmental toxins, but the toxins were man-made chemicals,” Inamdar said. “In this paper, we show that biologic compounds have the potential to damage dopamine and cause Parkinson’s symptoms.”

For co-author Bennett, the research was more than academic. Bennett was working at Tulane University in New Orleans when Hurricane Katrina struck the Gulf Coast in 2005. Her flooded house became infested with molds, which she collected in samples, wearing a mask, gloves and protective gear.

“I felt horrible – headaches, dizziness, nausea,” said Bennett, now a professor of plant pathology and biology at Rutgers. “I knew something about ‘sick building syndrome’ but until then I didn’t believe in it.  I didn’t think it would be possible to breathe in enough mold spores to get sick.” That is when she formed her hypothesis that volatiles might be involved.

Inamdar, who uses fruit flies in her research, and Bennett began their study shortly after Bennett arrived at Rutgers. Bennett wanted to understand the connection between molds and symptoms like those she had experienced following Katrina. 

The scientists discovered that the volatile organic compound 1-octen-3-ol, otherwise known as mushroom alcohol, can cause movement disorders in flies, similar to those observed in the presence of pesticides, such as paraquat and rotenone. Further, they discovered that it attacked two genes that deal with dopamine, degenerating the neurons and causing the Parkinson’s-like symptoms. 

Studies indicate that Parkinson’s disease – a progressive disease of the nervous system marked by tremor, muscular rigidity and slow, imprecise movement — is increasing in rural areas, where it’s usually attributed to pesticide exposure. But rural environments also have a lot of mold and mushroom exposure.

“Our work suggests that 1-octen-3-ol might also be connected to the disease, particularly for people with a genetic susceptibility to it,” Inamdar said. “We’ve given the epidemiologists some new avenues to explore.”

(Source: news.rutgers.edu)

A Columbia University Medical Center-led research team has clinically validated a new method for predicting time to full-time care, nursing home residence, or death for patients with Alzheimer’s disease. The method, which uses data gathered from a single patient visit, is based on a complex model of Alzheimer’s disease progression that the researchers developed by consecutively following two sets of Alzheimer’s patients for 10 years each. The results were published online ahead of print in the Journal of Alzheimer’s Disease.

“Predicting Alzheimer’s progression has been a challenge because the disease varies significantly from one person to another—two Alzheimer’s patients may both appear to have mild forms of the disease, yet one may progress rapidly, while the other progresses much more slowly,” said senior author Yaakov Stern, PhD, professor of neuropsychology (in neurology, psychiatry, and psychology and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center) at CUMC. “Our method enables clinicians to predict the disease path with great specificity.”

(Source: newsroom.cumc.columbia.edu)

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Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary. There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival, Rothstein notes.

(Source: hopkinsmedicine.org)

Faced with news of suicides and brain damage in former professional football players, geneticist Barry Ganetzky bemoaned the lack of model systems for studying the insidious and often delayed consequences linked to head injuries.

Then he remembered an unexplored observation from nearly 40 years ago: a sharp strike to a vial of fruit flies left them temporarily stunned, only to recover a short time later. At the time he had marked it only as a curiosity.

Now a professor of genetics at UW–Madison, Ganetzky is turning his accidental discovery into a way to study traumatic brain injury (TBI). He and David Wassarman, a UW professor of cell and regenerative biology, report this week (Oct. 14) in the Proceedings of the National Academy of Sciences on the first glimpses of the genetic underpinnings of susceptibility to brain injuries and links to human TBI.

TBIs occur when a force on the body jostles the brain inside the head, causing it to strike the inside of the skull. More than 1.7 million TBIs occur each year in the United States, about one-third due to falls and the rest mainly caused by car crashes, workplace accidents, and sports injuries. TBIs are also a growing issue in combat veterans exposed to explosions.

In many cases, the immediate effects of TBI are temporary and may seem mild — confusion, dizziness or loss of coordination, headaches, vision problems. But over time, impacts may lead to neurodegeneration and related symptoms, including memory loss, cognitive problems, severe depression, or Alzheimer’s-like dementia. Together TBIs cost tens of billions of dollars annually in medical expenses and indirect costs such as lost productivity.

Though TBIs can be classified from “mild” to “severe” based on symptoms, there is a poor understanding of the underlying medical causes.

“Unlike many important medical problems — high blood pressure, cancer, diabetes, heart disease — where we know something about the biology, we know almost nothing about TBI,” Ganetzky says. “Why does a blow to the head cause epilepsy? Or how does it lead down the road to neurodegeneration? Nobody has answers to those questions — in part, because it’s really hard to study in humans.”

Enter the fruit fly. The fly brain is encased in a hard cuticle analogous to the skull, and the basic mechanisms affecting nervous system function are the same in flies and mammals. In the new study, Ganetzky and Wassarman describe a way to reproducibly inflict traumas that seem to mimic the injuries and symptoms of human TBI.

“Now we have a system where we can look at the variables that are the inputs into TBI and determine the relative contributions of each to the pathological outcomes. That’s the real power of the flies,” says Wassarman.

As with humans, few flies die from the immediate impact. Afterward, though, the treated flies show many of the same physical consequences as humans who sustain concussions or other TBIs, including temporary incapacitation, loss of coordination and activation of the innate immune response in the short term, followed by neurodegeneration and sometimes an early death.

The researchers, led by Rebeccah Katzenberger, senior research specialist in the UW Department of Cell and Regnerative Biology, also found that age seems to play an important role. Older flies are more susceptible than younger ones to the effects of the impact and, Wassarman says, many of the outcomes of TBI are very similar to normal aging processes.

With this model, the researchers say, they can now draw on the vast collection of genetic tools and techniques available for fruit flies to probe the underlying drivers of damage.

“What we really want is to understand the immediate and long term consequences in cellular and molecular terms,” says Ganetzky. “From that understanding we can proceed in a more directed way to diagnostics and therapeutics.”

One of the key things they have already identified is the crucial role genetics plays in determining the outcome of an injury, revealed by the high degree of variability seen among different strains of flies. This finding may explain why all potential TBI drugs to date have failed in clinical trials despite showing promise in individual rodent models.

As Wassarman explains, “The heart of the problem of solving traumatic brain injury is that we’re all different.”

They are continuing to develop the model through large-scale genetic analysis and have already found that different sets of genes correlate with susceptibility in flies of different ages. With their system, they can also examine the effects of repeated injuries.

Ganetzky sees tremendous potential for developing applications from the fly-based approach and the Wisconsin Alumni Research Foundation (WARF) has filed for patent protection on the discovery.

“These exciting findings that we can study traumatic brain injury — a disorder of growing concern for athletes, the military, and parents — in the elegantly simple model of fruit flies is sure to interest those researchers and companies looking to address this concern,” says Jennifer Gottwald, WARF licensing manager. “The use of this model can accelerate the work of the medical research community in finding treatments and therapies to help patients.”

(Source: news.wisc.edu)

A diagnosis of multiple sclerosis (MS) is a hard lot. Patients typically get the diagnosis around age 30 after experiencing a series of neurological problems such as blurry vision, wobbly gait or a numb foot. From there, this neurodegenerative disease follows an unforgiving course.

Many people with MS start using some kind of mobility aid — cane, walker, scooter or wheelchair — by 45 or 50, and those with the most severe cases are typically bed-bound by 60. The medications that are currently available don’t do much to slow the relentless march of the disease.

In search of a better option for MS patients, a team of UW-Madison biochemists has discovered a promising vitamin D-based treatment that can halt — and even reverse — the course of the disease in a mouse model of MS. The treatment involves giving mice that exhibit MS symptoms a single dose of calcitriol, the active hormone form of vitamin D, followed by ongoing vitamin D supplements through the diet. The protocol is described in a scientific article that was published online in August in the Journal of Neuroimmunology.

"All of the animals just got better and better, and the longer we watched them, the more neurological function they regained," says biochemistry professor Colleen Hayes, who led the study.

MS afflicts around 400,000 people nationwide, with 200 new cases diagnosed each week. Early on, this debilitating autoimmune disease, in which the immune system attacks the myelin coating that protects the brain’s nerve cells, causes symptoms including weakness, loss of dexterity and balance, disturbances to vision, and difficulty thinking and remembering. As it progresses, people can lose the ability to walk, sit, see, eat, speak and think clearly.

Current FDA-approved treatments only work for some MS patients and, even among them, the benefits are modest. “And in the long term they don’t halt the disease process that relentlessly eats away at the neurons,” Hayes adds. “So there’s an unmet need for better treatments.”

While scientists don’t fully understand what triggers MS, some studies have linked low levels of vitamin D with a higher risk of developing the disease. Hayes has been studying this “vitamin D hypothesis” for the past 25 years with the long-term goal of uncovering novel preventive measures and treatments. Over the years, she and her researchers have revealed some of the molecular mechanisms involved in vitamin D’s protective actions, and also explained how vitamin D interactions with estrogen may influence MS disease risk and progression in women.

In the current study, which was funded by the National Multiple Sclerosis Society, Hayes’ team compared various vitamin D-based treatments to standard MS drugs. In each case, vitamin D-based treatments won out. Mice that received them showed fewer physical symptoms and cellular signs of disease.

First, Hayes’ team compared the effectiveness of a single dose of calcitriol to that of a comparable dose of a glucocorticoid, a drug now administered to MS patients who experience a bad neurological episode. Calcitriol came out ahead, inducing a nine-day remission in 92 percent of mice on average, versus a six-day remission in 58 percent for mice that received glucocorticoid.

"So, at least in the animal model, calcitriol is more effective than what’s being used in the clinic right now," says Hayes.

Next, Hayes’ team tried a weekly dose of calcitriol. They found that a weekly dose reversed the disease and sustained remission indefinitely.

But calcitriol can carry some strong side effects — it’s a “biological sledgehammer” that can raise blood calcium levels in people, Hayes says — so she tried a third regimen: a single dose of calcitriol, followed by ongoing vitamin D supplements in the diet. This one-two punch “was a runaway success,” she says. “One hundred percent of mice responded.”

Hayes believes that the calcitriol may cause the autoimmune cells attacking the nerve cells’ myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place.

While she is excited about the prospect of her research helping MS patients someday, Hayes is quick to point out that it’s based on a mouse model of disease, not the real thing. Also, while rodents are genetically homogeneous, people are genetically diverse.

"So it’s not certain we’ll be able to translate (this discovery to humans)," says Hayes. "But I think the chances are good because we have such a broad foundation of data showing protective effects of vitamin D in humans."

The next step is human clinical trials, a step that must be taken by a medical doctor, a neurologist. If the treatment works in people, patients with early symptoms of MS may never need to receive an official diagnosis.

"It’s my hope that one day doctors will be able to say, ‘We’re going to give you an oral calcitriol dose and ramp up the vitamin D in your diet, and then we’re going to follow you closely over the next few months. You’re just going to have this one neurological episode and that will be the end of it,’" says Hayes. "That’s my dream."

(Source: news.wisc.edu)