Neuroscience

Researchers have found new evidence that insulating cells, the cells that protect our nerves, can be made and added to the central nervous system throughout our lifetime.

Chief investigator on the paper, Menzies Research Institute Tasmania’s Dr Kaylene Young, says there is now evidence that these cells may not be the passive by-standers to brain function that we once thought.

“Previously it was thought that most insulating cells in an adult brain were born before reaching adulthood,” Dr Young said.

“This research shows that new insulating cells are made from an immature cell type found in our brains, called oligodendrocyte precursor cells (OPCs).

“In fact, new insulation is added to brain circuits every day, which changes the way the circuits function. 

“This process is likely to be very important for learning, memory, vision and co-ordination.”

“This finding may have important implications for sufferers of Alzheimer’s Disease, multiple sclerosis and other neurological disorders.

Alzheimer’s disease is the most common form of dementia. There are over 321,600 Australians living with dementia and without a medical breakthrough, the number of people with dementia is expected to be almost 900,000 by 2050. (Alzheimer’s Australia)

In Alzheimer’s Disease (AD) many nerve cells die. This causes patients with AD to progressively lose their ability to think clearly and remember things, and they can also experience problems with movement and co-ordination.

A single insulating cell in the brain supports the health and function of many nerve cells.

We know from diseases like multiple sclerosis that losing insulation makes nerve cells extremely vulnerable to damage and death.

This may also be true for AD, and there is an increasing amount of evidence that supports the idea that insulating cells are damaged before nerve cells and could contribute directly to nerve cell loss.

By studying brain scans from patients with AD, researchers previously found that the amount of insulation that is damaged matched the level of the patient’s dementia. The more damaged the insulation, the worse the person’s memory problems.

Dr Young’s research team are now investigating ways to hijack the natural ability of OPCs to make new insulating cells, and repair the insulation damage that is seen in the brains of AD patients.

“Stimulating OPCs in the brain is an appealing possibility since they are found throughout all brain regions, meaning that they are already where they need to be to make new insulating cells!

“We expect that increasing brain insulation, to re-wrap the nerve cells, will prevent more nerve cells from dying. Protecting nerve cells would prevent the rapid mental deterioration seen in people after they are diagnosed with AD,” Dr Young said.

This work was published this month, in the international journal, Neuron and involved collaboration with researchers in the United Kingdom and Japan.

Innovative medical records software developed by geriatricians and informaticians from the Regenstrief Institute and the Indiana University Center for Aging Research will provide more personalized health care for older adult patients, a population at significant risk for mental health decline and disorders.

A new study published in eGEMs, a peer-reviewed online publication recently launched by the Electronic Data Methods Forum, unveils the enhanced Electronic Medical Record Aging Brain Care Software, an automated decision-support system that enables care coordinators to track the health of the aging brain and help meet the complex biopsychosocial needs of patients and their informal caregivers.

The eMR-ABC captures and monitors the cognitive, functional, behavioral and psychological symptoms of older adults suffering from dementia or depression. It also collects information on the burden placed on patients’ family caregivers.

Utilizing this information, the software application provides decision support to care coordinators, who, working with physicians, social workers and other members of the health care team, create a personalized care plan that includes evidence-based non-pharmacological protocols, self-management handouts and alerts of medications with potentially adverse cognitive effects. The software’s built-in engine tracks patient visits and can be used to generate population reports for specified indicators such as cognitive decline or caregiver burnout.

"The number of older adults is growing rapidly. Delivering personalized care to this population is difficult and requires the ability to track a large number of mental and physical indicators," said Regenstrief Institute investigator Malaz Boustani, M.D., MPH, associate director of the IU Center for Aging Research and associate professor of medicine at the IU School of Medicine. He is senior author of the new study. "The software we have developed will help care coordinators measure the many needs of patients and their loved ones and monitor the effectiveness of individualized care plans."

In clinical trials over the past decade, Regenstrief and the IU Center for Aging Research investigator-clinicians developed and demonstrated the efficacy of an Alzheimer’s disease collaborative care model called the Aging Brain Care Medical Home. A hallmark of the ABC-MedHome is the employment of care coordinators who help clinicians identify and manage processes and protocols for Alzheimer’s patients who receive care in local primary care physician offices. The ABC-MedHome has been shown to improve the quality of Alzheimer’s care and decrease its burden on the health care system.

Within the ABC-MedHome program, Dr. Boustani and colleagues have now developed, tested, implemented and improved software that is sensitive to the clinical needs of a multispecialty team of professionals who provide care to complex patients across a variety of settings. The new software allows tracking of individual patient health outcomes as well as the ability to follow the status of an entire patient population with key quality, health and cost metrics.

"Integration of the eMR-ABC program within Wishard-Eskenazi Health was pivotal to our receipt in 2012 of a Health Care Innovation Challenge award from the Centers for Medicare & Medicaid Services to expand from care of 250 patients to 2,000 patients plus caregivers," said Dr. Boustani, who is medical director of the Wishard Healthy Aging Brain Center and also an IU Health geriatrician. "New models of care, supported by population health management tools, are needed if we are to provide improved quality of care and encourage better health outcomes for our patients and be cost sensitive. We are using health information technology to manage high-risk populations while achieving the triple aim of better health and better care at lower cost."

Since the 1960s, psychiatrists have been hunting for substances made by the body that might accumulate in abnormally high levels to produce the symptoms associated with schizophrenia. In particular, there was a search for chemicals that might be related to the hallucinogens phencyclidine (PCP) or lysergic acid diethylamide (LSD), which could explain the emergence of psychotic symptoms in schizophrenia. This “auto-intoxication” hypothesis led investigators on a wild goose chase where substances, including the “Pink Spot” and the “Frohman Factor”, were isolated from people with schizophrenia and implicated in their illness, but these findings were later discredited.

The mysterious GRIN3A is a new version of the hunt for an intrinsic mechanism that produces schizophrenia-like symptoms. GRIN3A is a gene that codes for the GluN3A subunit of the N-methyl-D-aspartate-type (NMDA) receptor, a target for the neurotransmitter glutamate in the brain. Functional NMDA receptors usually have two GluN1 subunits and two GluN2 subunits. The ability of glutamate to activate these receptors is blocked by PCP and the anesthetic/hallucinogen, ketamine. When the GluN3A subunit is incorporated, it prevents the NMDA receptor from being activated by glutamate, almost as if the receptor had been blocked by PCP.

It is unclear why the brain needs this mechanism for normal brain development and function, hence the mystery surrounding GRIN3A. One piece of evidence supporting a link between GluN3A and schizophrenia is the finding that GluN3A levels are elevated in the post-mortem brain tissue from people who had been diagnosed with schizophrenia.

In this issue of Biological Psychiatry, Japanese researchers led by Dr. Takeo Yoshikawa provide new support for this hypothesis by implicating variation in GRIN3A in the heritable risk for schizophrenia.

Schizophrenia is thought to have a substantial genetic background which is, to some extent, population-specific. Genome-wide searches have revealed many common genomic variants with weak effects, but the remaining “missing heritability” is largely unknown. Scientists theorize that it may be partly explained by rare variants with large effect.

To identify genetic variants with larger effect sizes, Yoshikawa and his colleagues examined genetic data from several Asian populations. They identified a rare variant in GRIN3A with study-wide significance.

"This discovery is important, because the ‘NMDA receptor hypothesis’ for schizophrenia is a common disease model," said Yoshikawa. "We propose a novel point of therapeutic intervention in the NMDA receptor signaling system for schizophrenia."

Dr. John Krystal, Editor of Biological Psychiatry, commented, “The notion that a genetic trait that acts like PCP in the brain produces schizophrenia is a very attractive but over-simplistic hypothesis. It is that the biology of schizophrenia is much more complicated than this single factor. Nonetheless, perhaps this study of GRIN3A brings us another step closer to understanding glutamate abnormalities in schizophrenia.”

Researchers in the UK have taken an important step towards understanding how the human brain ‘decodes’ letters on a page to read a word. The work, funded by the Economic and Social Research Council (ESRC), will help psychologists unravel the subtle thinking mechanisms involved in reading, and could provide solutions for helping people who find it difficult to read, for example in conditions such as dyslexia.

In order to read successfully, readers need not only to identify the letters in words, but also to accurately code the positions of those letters, so that they can distinguish words like CAT and ACT. At the same time, however, it’s clear that raeders can dael wtih wodrs in wihch not all teh leettrs aer in thier corerct psotiions.

"How the brain can make sense of some jumbled sequences of letters but not others is a key question that psychologists need to answer to understand the code that the brain uses when reading," says Professor Colin Davis of Royal Holloway, University of London, who led the research.

For many years researchers have used a standard psychological test to try to work out which sequences of letters in a word are important cues that the brain uses, where jumbled words are flashed momentarily on a screen to see if they help the brain to recognise the properly spelt word.

But, this technique had limitations that made it impossible to probe more extreme rearrangements of sequences of letters. Professor Davis’s team used computer simulations to work out that a simple modification to the test would allow it to question these more complex changes to words. This increases the test’s sensitivity significantly and makes it far more valuable for comparing different coding theories.

"For example, if we take the word VACATION and change it to AVACITNO, previously the test would not tell us if the brain recognises it as VACATION because other words such as AVOCADO or AVIATION might start popping into the person’s head,” says Professor Davis. "With our modification we can show that indeed the brain does relate AVACITNO to VACATION, and this starts to give us much more of an insight into the nature of the code that the brain is using – something that was not possible with the existing test."

The modified test should allow researchers not only to crack the code that the brain uses to make sense of strings of letters, but also to examine differences between individuals – how a ‘good’ reader decodes letter sequences compared with someone who finds reading difficult.

"These kinds of methods can be very sensitive to individual differences in reading ability and we are starting to get a better idea of some of the issues that underpin people’s difficulty in reading," says Professor Davis. Ultimately, this could lead to new approaches to helping people to overcome reading problems.

For the first time, scientists have transplanted neural cells derived from a monkey’s skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says, “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”

The cells were implanted in the monkeys “using a state-of-the-art surgical procedure” guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson’s disease, which afflicts up to 1 million Americans. Parkinson’s is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain.

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.

In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process. “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells.”

Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants. “Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibers], as we’d expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”

The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal’s behavior did not improve.

Although promising, the transplant technique is a long way from the clinic, Zhang adds. “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough… And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”

Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine.”

The need for treatment is incessant, says Emborg, noting that each year, Parkinson’s is diagnosed in 60,000 patients. “I’m gratified that the Parkinson’s Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease.”

"It’s really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang. "I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."

An iron imbalance caused by prion proteins collecting in the brain is a likely cause of cell death in Creutzfeldt-Jakob disease (CJD), researchers at Case Western Reserve University School of Medicine have found.

The breakthrough follows discoveries that certain proteins found in the brains of Alzheimer’s and Parkinson’s patients also regulate iron. The results suggest that neurotoxicity by the form of iron, called redox-active iron, may be a trait of neurodegenerative conditions in all three diseases, the researchers say.

Further, the role of the normal prion protein known as PrPc in iron metabolism may provide a target for strategies to maintain iron balance and reduce iron-induced neurotoxicity in patients suffering from CJD, a rare degenerative disease for which no cure yet exists.

The researchers report that lack of PrPC hampers iron uptake and storage and more findings are now in the online edition of the Journal of Alzheimer’s Disease.

"There are many skeptics who think iron is a bystander or end-product of neuronal death and has no role to play in neurodegenerative conditions," said Neena Singh, a professor of pathology and neurology at Case Western Reserve and the paper’s senior author. "We’re not saying that iron imbalance is the only cause, but failure to maintain stable levels of iron in the brain appears to contribute significantly to neuronal death."

Prions are misfolded forms of PrPC that are infectious and disease-causing agents of CJD. PrPc is the normal form present in all tissues including the brain. PrPc acts as a ferrireductase, that is, it helps to convert oxidized iron to a form that can be taken up and utilized by the cells, the scientists show.

In their investigation, mouse models that lacked PrPC were iron-deficient. By supplementing their diets with excess inorganic iron, normal levels of iron in the body were restored. When the supplements stopped, the mice returned to being iron-deficient.

Examination of iron metabolism pathways showed that the lack of PrPC impaired iron uptake and storage, and alternate mechanisms of iron uptake failed to compensate for the deficiency.

Cells have a tight regulatory system for iron uptake, storage and release. PrPC is an essential element in this process, and its aggregation in CJD possibly results in an environment of iron imbalance that is damaging to neuronal cells, Singh explained

It is likely that as CJD progresses and PrPC forms insoluble aggregates, loss of ferrireductase function combined with sequestration of iron in prion aggregates leads to insufficiency of iron in diseased brains, creating a potentially toxic environment, as reported earlier by this group and featured in Nature Journal club.

Recently, members of the Singh research team also helped to identify a highly accurate test to confirm the presence of CJD in living sufferers. They found that iron imbalance in the brain is reflected as a specific change in the levels of iron-management proteins other than PrPc in the cerebrospinal fluid. The fluid can be tapped to diagnose the disease with 88.9 percent accuracy, the researchers reported in the journal Antioxidants & Redox Signaling online last month.

Singh’ s team is now investigating how prion protein functions to convert oxidized iron to a usable form. They are also evaluating the role of prion protein in brain iron metabolism, and whether the iron imbalance observed in cases of CJD, Alzheimer’s disease and Parkinson’s disease is reflected in the cerebrospinal fluid. A specific change in the fluid could provide a disease-specific diagnostic test for these disorders.

Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia and depression. In schizophrenia, deficits have been particularly well-described for a subtype of GABA neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical for proper cognitive and emotional functioning.

It now appears that parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that may emerge commonly in development, particularly in the context of psychiatric disorders like schizophrenia or bipolar disorder, where compromised mitochondrial function plays a role. parvalbumin neurons may be protected from this effect by N-acetylcysteine, also known as Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of acetaminophen (Tylenol) overdose, reports a new study in the current issue of Biological Psychiatry.

Dr. Kim Do and collaborators, from the Center for Psychiatric Neurosciences of Lausanne University in Switzerland, have worked many years on the hypothesis that one of the causes of schizophrenia is related to vulnerability genes/factors leading to oxidative stress. These oxidative stresses can be due to infections, inflammations, traumas or psychosocial stress occurring during typical brain development, meaning that at-risk subjects are particularly exposed during childhood and adolescence, but not once they reach adulthood.

Their study was performed with mice deficient in glutathione, a molecule essential for cellular protection against oxidations, leaving their neurons more exposed to the deleterious effects of oxidative stress. Under those conditions, they found that the parvalbumin neurons were impaired in the brains of mice that were stressed when they were young. These impairments persisted through their life. Interestingly, the same stresses applied to adults had no effect on their parvalbumin neurons.

Most strikingly, mice treated with the antioxidant N-acetylcysteine, from before birth and onwards, were fully protected against these negative consequences on parvalbumin neurons.

“These data highlight the need to develop novel therapeutic approaches based on antioxidant compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects,” said Do. “To give an antioxidant from childhood on to carriers of a genetic vulnerability for schizophrenia could reduce the risk of emergence of the disease.”

“This study raises the possibility that GABA neuronal deficits in psychiatric disorder may be preventable using a drug, N-acetylcysteine, which is quite safe to administer to humans,” added Dr. John Krystal, Editor of Biological Psychiatry.

Newly released findings from Bradley Hospital published in the Journal of the American Academy of Child & Adolescent Psychiatry have found that autism spectrum disorders (ASD) affect the brain activity of children and adults differently.

In the study, titled “Developmental Meta-Analysis of the Functional Neural Correlates of Autism Spectrum Disorders,” Daniel Dickstein, M.D., FAAP, director of the Pediatric Mood, Imaging and Neurodevelopment Program at Bradley Hospital, found that autism-related changes in brain activity continue into adulthood.

"Our study was innovative because we used a new technique to directly compare the brain activity in children with autism versus adults with autism," said Dickstein. "We found that brain activity changes associated with autism do not just happen in childhood, and then stop. Instead, our study suggests that they continue to develop, as we found brain activity differences in children with autism compared to adults with autism. This is the first study to show that."

This new technique, a meta-analysis, which is a study that compiles pre-existing studies, provided researchers with a powerful way to look at potential differences between children and adults with autism.

Dickstein conducted the research through Bradley Hospital’s PediMIND Program. Started in 2007, this program seeks to identify biological and behavioral markers—scans and tests—that will ultimately improve how children and adolescents are diagnosed and treated for psychiatric conditions. Using special computer games and brain scans, including magnetic resonance imaging (MRI), Dickstein hopes to one day make the diagnosis and treatment of autism and other disorders more specific and more effective.

Among autism’s most disabling symptoms is a disruption in social skills, so it is noteworthy that this study found significantly less brain activity in autistic children than autistic adults during social tasks, such as looking at faces. This was true in brain regions including the right hippocampus and superior temporal gyrus—two brain regions associated with memory and other functions.

Dickstein noted, “Brain changes in the hippocampus in children with autism have been found in studies using other types of brain scan, suggesting that this might be an important target for brain-based treatments, including both therapy and medication that might improve how this brain area works.”

Rowland Barrett, Ph.D., chief psychologist at Bradley Hospital and chief-of-service for The Center for Autism and Developmental Disabilities was also part of the team leading the study.

"Autism spectrum disorders, including autistic disorder, Asperger’s disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS), are among the most common and impairing psychiatric conditions affecting children and adolescents today," said Barrett. "If we can identify the shift in the parts of the brain that autism affects as we age, then we can better target treatments for patients with ASD."

Cognitive impairments are disabling for individuals with schizophrenia, and no satisfactory treatments currently exist. These impairments affect a wide range of cognition, including memory, attention, verbal and motor skills, and IQ. They appear in the earliest stages of the disease and disrupt or even prevent normal day-to-day functioning.

Scientists are exploring a variety of strategies to reduce these impairments including “exercising the brain” with specially designed computer games and medications that might improve the function of brain circuits.

In this issue of Biological Psychiatry, Dr. Mera Barr and her colleagues at University of Toronto provide new evidence that stimulating the brain using repetitive transcranial magnetic stimulation (rTMS) may be an effective strategy to improve cognitive function.

“In a randomized controlled trial, we evaluated whether rTMS can improve working memory in schizophrenia,” said Barr and senior author Dr. Zafiris Daskalakis. “Our results showed that rTMS resulted in a significant improvement in working memory performance relative to baseline.”

Transcranial magnetic stimulation is a non-invasive procedure that uses magnetic fields to stimulate nerve cells. It does not require sedation or anesthesia and so patients remain awake, reclined in a chair, while treatment is administered through coils placed near the forehead.

“TMS can have lasting effects on brain circuit function because this approach not only changes the activity of the circuit that is being stimulated, but it also may change the plasticity of that circuit, i.e., the capacity of the circuit to remodel itself functionally and structurally to support cognitive functions,” explained Dr. John Krystal, Editor of Biological Psychiatry.

Previous work has shown that rTMS improves working memory in healthy individuals and a recent open-label trial showed promising findings for verbal memory in schizophrenia patients. This series of findings led this study to determine if high frequency rTMS could improve memory in individuals with schizophrenia.

They recruited medicated schizophrenia patients who completed a working memory task before and after 4 weeks of treatment. Importantly, this was a double-blind study, where neither the patients nor the researchers knew who was receiving real rTMS or a sham treatment that was designed to entirely mimic the procedure without actually delivering brain stimulation.

rTMS not only improved working memory in patients after 4 weeks, but the improvement was to a level comparable to healthy subjects. These findings suggest that rTMS may be a novel, efficacious, and safe treatment for working memory deficits in schizophrenia.

In 2008, rTMS was FDA-approved to treat depression for individuals who don’t respond to pharmacotherapy. The hope is that additional research will replicate these findings and finally provide an approved treatment for cognitive impairments in schizophrenia.

The authors concluded: “Working memory is an important predictor of functional outcome. Developing novel treatments aimed at improving these deficits may ultimately translate into meaningful changes in the lives of patients suffering from this debilitating disorder.”

A research team led by Robert Nagele, PhD, of the New Jersey Institute for Successful Aging (NJISA) at the University of Medicine and Dentistry of New Jersey (UMDNJ)-School of Osteopathic Medicine, has demonstrated that the anti-atherosclerosis drug darapladib can significantly reduce leaks in the blood brain barrier. This finding potentially opens the door to new therapies to prevent the onset or the progression of Alzheimer’s disease. Writing in the Journal of Alzheimer’s Disease (currently in press), the researchers describe findings involving the use of darapladib in animal models that had been induced to develop diabetes mellitus and hypercholesterolemia (DMHC), which are considered to be major risk factors for Alzheimer’s disease.

“Diabetes and hypercholesterolemia are associated with an increased permeability of the blood-brain barrier, and it is becoming increasingly clear that this blood-brain barrier breakdown contributes to neurodegenerative diseases such as Alzheimer’s,” Nagele said. “Darapladib appears to be able to reduce this permeability to levels comparable to those found in normal, non-DMHC controls, and suggests a link between this permeability and the deposition of amyloid peptides in the brain.”

The study involved 28 animal (pig) models that were divided into three groups – DMHC animals treated with a 10 mg/day dose of darapladib; DMHC animals that received no treatment; and non-DMHC controls. Post-mortem analysis of the brains of the darapladib-treated animals showed significant decreases in blood-brain barrier leakage and in the density of amyloid-positive neurons in the cerebral cortices. Interestingly, the amyloid peptides that leaked into the brain tissue were found almost exclusively in the pyramidal neurons of the cerebral cortex, one of the earliest pathologies of the development of Alzheimer’s disease.

“Because our results suggest that these metabolic disorders can trigger neurodegenerative changes through blood-brain barrier compromise, therapies – such as darapladib – that can reduce vascular leaks have great potential for delaying the onset or slowing the progression of diseases like Alzheimer’s,” said the study’s lead author, Nimish Acharya, PhD, of the NJISA and the UMDNJ-Graduate School of Biomedical Sciences. “The clinical, caregiving and financial impact of such an effect cannot be overestimated.”

The British astrophysicist Stephen Hawking is likely to be the world’s most famous person living with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a progressive disease affecting motor neurons, nerve cells that control muscle function, and nearly always leads to death. Researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna have now identified a completely new mechanism in the onset of motor neuron diseases. Their findings could be the basis for future treatments for these presently incurable diseases.

A new principle on motor neuron death
The IMBA scientists, working with an international team of researchers under the leadership of Josef Penninger and Javier Martinez, discovered a completely new fundamental mechanism that triggers the death of motor neurons. Motor neurons are nerve cells responsible for stimulating muscles. The loss of these motor neurons in mice with a genetic mutation in a gene named CLP11 leads to severe and progressive muscular paralysis and, in some cases, to death.
"We’ve been working on resolving the function of the CLP1 gene in a living organism for a long time. To do that, we developed model mice in which the function of CLP1 was genetically inactivated. To our utter surprise we discovered that deactivating CLP1 increases the sensitivity of cell die when exposed to oxidative stress2. That leads to enhanced activity of the p53 protein3 and then to the permanent destruction of motor neurons," says Toshikatsu Hanada, a postdoctoral researcher working in the lab of Josef Penninger and first author of the study along with Stefan Weitzer.

Stephen Hawking - a most renowned patient
Motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are chronic disorders of the neuromuscular system. These diseases are caused by damage in the motor nerve cells in the brain and spinal cord, and the nerves can no longer stimulate motion in the muscles. The primary symptoms are muscular weakness, muscular dystrophy, and problems swallowing or speaking. Stephen Hawking was diagnosed with ALS 50 years ago. But not all ALS patients live so long with the disease: so far there are no treatments for ALS. Nearly all ALS patients die of paralysis of respiratory muscles within a few years.

Completely new disease mechanism
Javier Martinez, an IMBA team leader and co-author of the study, is a specialist in the field of ribonucleic acid (RNA) research. His research group had discovered the CLP1 gene in an earlier study, published in Nature in 2007. Until now, the exact essential function of CLP1 in RNA biology was unclear. “By deactivating CLP1, we have discovered a previously unknown new species of RNA,” says Javier Martinez about the scientific relevance of the work. “The accumulation of this RNA is a consequence of increased oxidative stress in the cell. We see this as one of the triggers for the loss of motor neurons that occurs in ALS and other neuromuscular diseases. Thus our findings describe a completely new mechanism of motor neuron diseases.”

Seminal findings
Josef Penninger, scientific director at the IMBA and last-author of the study, is excited about the researchers’ findings: “This surprising discovery of a role of CLP1 in the onset of motor neuron diseases is an entirely new principle in how RNA talks to oxidative stress. Nearly all genetic mutations found in ALS patients affect either RNA metabolism or oxidative stress, suggesting a possibly unifying principle for these diseases. Our work may have revealed the ‘missing link’ in how these two biological systems communicate and trigger incurable diseases like ALS.”

Stefan Weitzer sees tremendous potential for these findings: “We’ve discovered a new mechanism that leads to the death of motor neurons. If this holds true for other neuronal disease, our results could be one day used to drive the development of treatments for previously incurable diseases. In our work we also describe how the p53 protein regulates the loss of motor neurons. Removing p53 saves mice with CLP1 mutations from certain death.” If scientists are successful in applying these findings to people, the researchers may have discovered a treatment approach to cure ALS and similar diseases. The authors, however, caution that more studies will be needed to translate their findings to human medicine.

This study was performed in collaboration with research groups from the Medical Universities of Vienna and Innsbruck, the University Medical Center at Hamburg-Eppendorf in Germany, the Harvard Medical School, the Harvard Stem Cell Institute, the Boston Children’s and Massachusetts General Hospitals, the Keio University School of Medicine in Tokyo, Oita University in Japan, and the Weizmann Institute of Science in Rehovot in Israel.

Their work, “CLP1 links tRNA metabolism to progressive motor-neuron loss”, was published on March 10, 2013 in “Nature”, an internationally renowned journal.