New clues to causes of peripheral nerve damage

Anyone whose hand or foot has “fallen asleep” has an idea of the numbness and tingling often experienced by people with peripheral nerve damage. The condition also can cause a range of other symptoms, including unrelenting pain, stinging, burning, itching and sensitivity to touch.

Although peripheral neuropathies afflict some 20 million Americans, their underlying causes are not completely understood. Much research has focused on the breakdown of cellular energy factories in nerve cells as a contributing factor.

Now, new research at Washington University School of Medicine in St. Louis points to a more central role in damage to energy factories in other cells: Schwann cells, which grow alongside neurons and enable nerve signals to travel from the spinal cord to the tips of the fingers and toes.

The finding may lead to new therapeutic strategies to more effectively treat symptoms of this highly variable disorder, the scientists report March 6 in the journal Neuron.

“We found that a toxic substance builds up in Schwann cells that have disabled energy factories, leading to the same kind of nerve damage seen in patients with neuropathies,” says senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor of Genetics and head of the Department of Genetics. “Now, we’re evaluating whether drugs can block the buildup of that toxin, which could lead to a new treatment for the condition.”

The most common cause of peripheral neuropathy is diabetes, which accounts for about half of all cases. The condition also can occur in cancer patients treated with chemotherapy, which can damage nerves.

In the body, Schwann cells wrap tightly around nerve axons, the fibers that relay nerve signals. Graduate student and first author Andreu Viader and colleagues in Milbrandt’s lab studied Schwann cells in mice with genetically disabled mitochondria, or cellular energy factories. Under normal conditions, these mitochondria produce fuel and intermediates of energy metabolism that allow nerve cells to function.

The researchers showed that the crippled mitochondria activated a stress response in the Schwann cells. Instead of synthesizing fatty acids, a key component of Schwann cells, the cells burned fatty acids for fuel.

Over time, inefficient burning of fatty acids by the crippled mitochondria leads to a build up of acylcarnitines, a toxic substance, in the Schwann cells. The researchers found levels of acylcarnitines up to 100-fold higher in these mutant Schwann cells than in healthy Schwann cells.

And the bad news doesn’t end there. Eventually, the toxin leaks out of the Schwann cells and onto the nerve axons. Studying neurons in petri dishes, the researchers showed that acylcarnitines damage nerve axons and disrupt the ability of nerves to relay signals.

“The toxin leaking out of the Schwann cells and onto the adjacent nerve axons causes damage that results in pain, numbness, tingling and other symptoms,” Milbrandt says. “We think that is a likely mechanism to explain the degeneration of axons that is known to occur in peripheral neuropathies.”

The new research suggests that drugs that inhibit the buildup of acylcarnitines may block axonal degeneration. Milbrandt and his team now are evaluating the drugs in mice with disabled Schwann cells to see if they can slow or alleviate the decay of axons.

Use It or Lose It

"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer’s disease. Previous studies have shown that keeping the mind active, exercising and social interactions may help delay the onset of dementia in Alzheimer’s disease.

Now, a new study led by Dennis Selkoe, MD, co-director of the Center for Neurologic Diseases in the Brigham and Women’s Hospital (BWH) Department of Neurology, provides specific pre-clinical scientific evidence supporting the concept that prolonged and intensive stimulation by an enriched environment, especially regular exposure to new activities, may have beneficial effects in delaying one of the key negative factors in Alzheimer’s disease.

The study will be published online on March 6, 2013 in Neuron.

Alzheimer’s disease occurs when a protein called amyloid beta accumulates and forms “senile plaques” in the brain. This protein accumulation can block nerve cells in the brain from properly communicating with one another. This may gradually lead to an erosion of a person’s mental processes, such as memory, attention, and the ability to learn, understand and process information.

The BWH researchers used a wild-type mouse model when evaluating how the environment might affect Alzheimer’s disease. Unlike other pre-clinical models used in Alzheimer’s disease research, wild-type mice tend to more closely mimic the scenario of average humans developing the disease under normal environmental conditions, rather than being strongly genetically pre-disposed to the disease.

Selkoe and his team found that prolonged exposure to an enriched environment activated certain adrenalin-related brain receptors which triggered a signaling pathway that prevented amyloid beta protein from weakening the communication between nerve cells in the brain’s “memory center,” the hippocampus. The hippocampus plays an important role in both short- and long-term memory.

The ability of an enriched, novel environment to prevent amyloid beta protein from affecting the signaling strength and communication between nerve cells was seen in both young and middle-aged wild-type mice.

"This part of our work suggests that prolonged exposure to a richer, more novel environment beginning even in middle age might help protect the hippocampus from the bad effects of amyloid beta, which builds up to toxic levels in one hundred percent of Alzheimer patients," said Selkoe.

Moreover, the scientists found that exposing the brain to novel activities in particular provided greater protection against Alzheimer’s disease than did just aerobic exercise. According to the researchers, this observation may be due to stimulation that occurred not only physically, but also mentally, when the mice moved quickly from one novel object to another.

"This work helps provide a molecular mechanism for why a richer environment can help lessen the memory-eroding effects of the build-up of amyloid beta protein with age," said Selkoe. "They point to basic scientific reasons for the apparent lessening of AD risk in people with cognitively richer and more complex experiences during life."

Scientists Identify ‘Clean-Up’ Snafu That Kills Brain Cells in Parkinson’s Disease

Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The study, which published online in the journal Nature Neuroscience, could also open up treatment possibilities for both familial Parkinson’s and the more common form of Parkinson’s that is not inherited.

"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein - the main component of those protein aggregates that gunk up nerve cells in Parkinson’s patients," said study leader Ana Maria Cuervo, M.D., Ph.D., professor of  developmental and molecular biology, of anatomy and structural biology, and of medicine and the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases at Einstein.

The name for the disrupted disposal process is chaperone-mediated autophagy (the word “autophagy” literally means “self-eating”). It involves specialized molecules that “guide” old and damaged proteins to enzyme-filled structures called lysosomes; there the proteins are digested into amino acids, which are then recycled within the cell.

"We showed that when LRRK2 inhibits chaperone-mediated autophagy,
alpha-synuclein doesn’t get broken down and instead accumulates to toxic levels in nerve cells,” said Dr. Cuervo.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with  LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.

"We’re now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease," said Dr. Cuervo. "We’ve started to analyze some chemical compounds that look very promising."

Dr. Cuervo hopes that such treatments could help patients with familial as well as nonfamilial Parkinson’s - the predominant form of the disease that also involves the buildup of alpha-synuclein.

Dr. Cuervo is credited with discovering chaperone-mediated autophagy. She has published extensively on autophagy and its role in numerous diseases, such as cancer and Huntington’s disease, and its role in age-related conditions, including organ decline and weakened immunity. Dr. Cuervo is co-director of Einstein’s  Institute of Aging Research.

(Image: Shutterstock)

Blood marrow derived cells regulate appetite

Bone marrow cells that produce brain-derived eurotrophic factor (BDNF), known to affect regulation of food intake, travel to part of the hypothalamus in the brain where they “fine-tune” appetite, said researchers from Baylor College of Medicine and Shiga University of Medical Science in Otsu, Shiga, Japan, in a report that appears online in the journal Nature Communications.

"We knew that blood cells produced BDNF," said Dr. Lawrence Chan, professor of molecular and cellular biology and professor and chief of the division of diabetes, endocrinology & metabolism in the department of medicine and director of the federally funded Diabetes Research Center, all at BCM. The factor is produced in the brain and in nerve cells as well. "We didn’t know why it was produced in blood cells."

Fluorescent marker reveals surprise

Dr. Hiroshi Urabe and Dr. Hideto Kojima, current and former postdoctoral fellows in Chan’s laboratory respectively, looked for BDNF in the brains of mice who had not been fed for about 24 hours. The bone marrow-derived cells had been marked with a fluorescent protein that showed up on microscopy. To their surprise, they found cells producing BDNF in a part of the brain’s hypothalamus called the paraventricular nucleus.

"We knew that in embryonic development, some blood cells do go to the brain and become microglial cells," said Chan. (Microglial cells form part of the supporting structure of the central nervous system. They are characterized by a nucleus from which "branches" expand in all directions.) "This is the first time we have shown that this happens in adulthood. Blood cells can go to one part of the brain and become physically changed to become microglial-like cells."

However, these bone marrow cells produce a bone marrow-specific variant of BDNF, one that is different from that produced by the regular microglial cells already in the hypothalamus.

Only a few of these blood-derived cells actually reach the hypothalamus, said Chan.

"It’s not very impressive if you look casually under the microscope," he said. However, a careful scrutiny showed that the branching nature of these cells allow them to come into contact with a whole host of brain cells.

"Their effects are amplified," said Chan.

Curbing the urge

Mice that are born lacking the ability to produce blood cells that make BDNF overeat, become obese and develop insulin resistance (a lack of response to insulin that affects the ability to metabolize glucose). A bone marrow transplant that restores the gene for making the cells that produce BDNF can normalize appetite, said Chan. However, a transplant of bone marrow that does not contain this gene does not reverse overeating, obesity or insulin resistance.

When normal bone marrow cells that produce BDNF are injected into the third ventricle (a fluid-filled cavity in the brain) of mice that lack BDNF, they no longer have the urge to overeat, said Chan.

All in all, the studies represent a new mechanism by which these bone-marrow derived cells control feeding through BDNF and could provide a new avenue to attack obesity, said Chan.

He and his colleagues hypothesize that the bone marrow cells that produce BDNF fine tune the appetite response, although a host of different appetite-controlling hormones produced by the regular nerve cells in the hypothalamus do the lion’s share of the work.

"Bone marrow cells are so accessible," said Chan. “If these cells play a regulatory role, we could draw some blood, modify something in it or add something that binds to blood cells and give it back. We may even be able to deliver medication that goes to the brain," crossing the blood-brain barrier. Even a few of these cells can have an effect because their geometry means that they have contact with many different neurons or nerve cells.

BPA May Affect the Developing Brain by Disrupting Gene Regulation

Environmental exposure to bisphenol A (BPA), a widespread chemical found in plastics and resins, may suppress a gene vital to nerve cell function and to the development of the central nervous system, according to a study led by researchers at Duke Medicine.

The researchers published their findings - which were observed in cortical neurons of mice, rats and humans - in the journal Proceedings of the National Academy of Sciences on Feb. 25, 2013.

"Our study found that BPA may impair the development of the central nervous system, and raises the question as to whether exposure could predispose animals and humans to neurodevelopmental disorders," said lead author Wolfgang Liedtke, M.D., PhD, associate professor of medicine/neurology and neurobiology at Duke.

BPA, a molecule that mimics estrogen and interferes with the body’s endocrine system, can be found in a wide variety of manufactured products, including thermal printer paper, some plastic water bottles and the lining of metal cans. The chemical can be ingested if it seeps into the contents of food and beverage containers.

Research in animals has raised concerns that exposure to BPA may cause health problems such as behavioral issues, endocrine and reproductive disorders, obesity, cancer and immune system disorders. Some studies suggest that infants and young children may be the most vulnerable to the effects of BPA, which led the U.S. Food and Drug Administration to ban the use of the chemical in baby bottles and cups in July 2012.

While BPA has been shown to affect the developing nervous system, little is understood as to how this occurs. The research team developed a series of experiments in rodent and human nerve cells to learn how BPA induces changes that disrupt gene regulation.

During early development of neurons, high levels of chloride are present in the cells. These levels drop as neurons mature, thanks to a chloride transporter protein called KCC2, which churns chloride ions out of the cells. If the level of chloride within neurons remains elevated, it can damage neural circuits and compromise a developing nerve cell’s ability to migrate to its proper position in the brain.

Exposing neurons to minute amounts of BPA alters the chloride levels inside the cells by somehow shutting down the Kcc2 gene, which makes the KCC2 protein, thereby delaying the removal of chloride from neurons.

MECP2, another protein important for normal brain function, was found to be a possible culprit behind this change. When exposed to BPA, MECP2 is more abundant and binds to the Kcc2 gene at a higher rate, which might help to shut it down. This could contribute to problems in the developing brain due to a delay in chloride being removed.

These findings raise the question of whether BPA could contribute to neurodevelopmental disorders such as Rett syndrome, a severe autism spectrum disorder that is only found in girls and is characterized by mutations in the gene that produces MECP2.

While both male and female neurons were affected by BPA in the studies, female neurons were more susceptible to the chemical’s toxicity. Further research will dig deeper into the sex-specific effects of BPA exposure and whether certain sex hormone receptors are involved in BPA’s effect on KCC2.

"Our findings improve our understanding of how environmental exposure to BPA can affect the regulation of the Kcc2 gene. However, we expect future studies to focus on what targets aside from Kcc2 are affected by BPA," Liedtke said. "This is a chapter in an ongoing story."

Cooling may prevent trauma-induced epilepsy

In the weeks, months and years after a severe head injury, patients often experience epileptic seizures that are difficult to control. A new study in rats suggests that gently cooling the brain after injury may prevent these seizures.

“Traumatic head injury is the leading cause of acquired epilepsy in young adults, and in many cases the seizures can’t be controlled with medication,” says senior author Matthew Smyth, MD, associate professor of neurological surgery and of pediatrics at Washington University School of Medicine in St. Louis. “If we can confirm cooling’s effectiveness in human trials, this approach may give us a safe and relatively simple way to prevent epilepsy in these patients.”

The researchers reported their findings in Annals of Neurology.

Cooling the brain to protect it from injury is not a new concept. Cooling slows down the metabolic activity of nerve cells, and scientists think this may make it easier for brain cells to survive the stresses of an injury. 

Doctors currently cool infants whose brains may have had inadequate access to blood or oxygen during birth. They also cool some heart attack patients to reduce peripheral brain damage when the heart stops beating.

Smyth has been exploring the possibility of using cooling to prevent seizures or reduce their severity.

“Warmer brain cells seem to be more electrically active, and that may increase the likelihood of abnormal electrical discharges that can coalesce to form a seizure,” Smyth says. “Cooling should have the opposite effect.”

Smyth and colleagues at the University of Washington and the University of Minnesota test potential therapies in a rat model of brain injury. These rats develop chronic seizures weeks after the injury.

Researchers devised a headset that cools the rat brain. They were originally testing its ability to stop seizures when they noticed that cooling seemed to be not only stopping but also preventing seizures.

Scientists redesigned the study to focus on prevention. Under the new protocols, they put headsets on some of the rats that cooled their brains by less than 4 degrees Fahrenheit. Another group of rats wore headsets that did nothing. Scientists who were unaware of which rats they were observing monitored them for seizures during treatment and after the headsets were removed.

Rats that wore the inactive headset had progressively longer and more severe seizures weeks after the injury, but rats whose brains had been cooled only experienced a few very brief seizures as long as four months after injury.

Brain injury also tends to reduce cell activity at the site of the trauma, but the cooling headsets restored the normal activity levels of these cells.

The study is the first to reduce injury-related seizures without drugs, according to Smyth, who is director of the Pediatric Epilepsy Surgery program at St. Louis Children’s Hospital.

“Our results show that the brain changes that cause this type of epilepsy happen in the days and weeks after injury, not at the moment of injury or when the symptoms of epilepsy begin,” says Smyth. “If clinical trials confirm that cooling has similar effects in humans, it could change the way we treat patients with head injuries, and for the first time reduce the chance of developing epilepsy after brain injury.”

Smyth and his colleagues have been testing cooling devices in humans in the operating room, and are planning a multi-institutional trial of an implanted focal brain cooling device to evaluate the efficacy of cooling on established seizures.

Fragile X makes brain cells talk too much

The most common inherited form of mental retardation and autism, fragile X syndrome, turns some brain cells into chatterboxes, scientists at Washington University School of Medicine in St. Louis report.

The extra talk may make it harder for brain cells to identify and attend to important signals, potentially establishing an intriguing parallel at the cellular level to the attention problems seen in autism.

According to the researchers, understanding the effects of this altered signaling will be important to developing successful treatments for fragile X and autism.

“We don’t know precisely how information is encoded in the brain, but we presume that some signals are important and some are noise,” says senior author Vitaly Klyachko, PhD, assistant professor of cell biology and physiology. “Our theoretical model suggests that the changes we detected may make it much more difficult for brain cells to distinguish the important signals from the noise.”

The findings appear Feb. 20 in Neuron.

Fragile X is caused by mutations in a gene called Fmr1. This gene is found on the X chromosome, one of the two sex chromosomes. Females have two copies of that chromosome, while males only have one. As a result, males have fragile X syndrome more often than females, and the effects in males tend to be more severe.

Symptoms of fragile X include mental retardation, hyperactivity, epilepsy, impulsive behavior, and delays in the development of speech and walking. Fragile X also affects anatomy, leading to unusually large heads, flat feet, large body size and distinctive facial features. Thirty percent of fragile X patients are autistic.

Scientists deleted the Fmr1 gene many years ago in mice to create a model of fragile X. Without Fmr1, the mice have abnormalities in brain cells and social and behavioral deficits similar to those seen in human fragile X.

According to Klyachko, nearly all fragile X mouse studies in the past two decades have focused on how Fmr1 loss affects dendrites, the branches of nerve cells that receive signals. In contrast, his new study finds significant changes in axons, the branches of nerve cells that send signals.

Normally, signals travel down the axon as surges of electrical energy. These surges only last for tiny fractions of a second, briefly causing the axon to release compounds known as neurotransmitters into the short gap between nerve cells. The neurotransmitters cross the gap and bind to their receptors on the dendrite to convey the signal.

When Klyachko monitored electrical surges along axons in the fragile X mice, though, he discovered that they lasted significantly longer. This caused release of more of neurotransmitters from the axon. When it should have stopped talking, the axon continued to chatter.

“The axons are putting out much more neurotransmitter than they should, and we think this confuses the system and overloads the circuitry,” Klyachko explains. “It may also create problems in terms of brain cells using up their resources much more quickly than they normally would.”

Infusing synthetic copies of the gene’s protein, called FMRP, into brain cells from the mouse model rapidly restored the electrical surges to their normal length.

Additional experiments revealed that FMRP works by interacting with one of the biggest channels on the surfaces of axons. These channels let electrically charged potassium ions into the axons, helping to shape and control the duration of the electrical surge.

In healthy brain cells, the main function of these channels is to prevent the electrical surge from getting too long. With FMRP gone, the channel is active for a shorter time, prolonging the surge and overwhelming the dendrite with too much chatter.

Klyachko and his colleagues are now studying the connections between FMRP and the channel it interacts with in axons. They hope to learn more about how information is encoded and processed at the level of individual brain cells. These insights one day may help clinicians better diagnose and treat many kinds of mental disorders.