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Dysfunction In Neuronal Transport Mechanism Linked To Alzheimer’s Disease

Researchers at University of California San Diego School of Medicine have confirmed that mutation-caused dysfunction in a process cells use to transport molecules within the cell plays a previously suspected but underappreciated role in promoting the heritable form of Alzheimer’s disease (AD), but also one that might be remedied with existing therapeutic enzyme inhibitors.

The findings published in the October 11 online issue of Cell Reports.

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD,” said the study’s senior author Larry Goldstein, PhD, Distinguished Professor in the Departments of Neuroscience and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of both the UC San Diego Stem Cell Program and Sanford Stem Cell Clinical Center at UC San Diego Health. “But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. It affects more than 30 million people worldwide, including an estimated 5.4 million Americans. One in 10 persons over the age of 65 has AD; one in three over the age of 85. There are currently no treatments proven to cure or reduce the progression of AD.

Genetically, AD is divided into two groups: the much more common sporadic (sAD) form of the disease in which the underlying primary cause is not known and the rarer familial (fAD) form, produced by inherited genetic mutations. In both forms, the brains of AD patients feature accumulations of protein plaques and neurofibrillary tangles that lead to neuronal impairment and eventual cell death.

The prevailing “amyloid cascade hypothesis” posits that these plaques and tangles are comprised, respectively, of amyloid precursor protein (APP) fragments and tau proteins that fuel cellular stress, neurotoxicity, loss of function and cell death. There has been some evidence, however, of another disease-driver: defects in endocytic trafficking — the process by which cells package large, external molecules into vesicles or membrane-bound sacs for transport into the cell for a variety of reasons or uses.

But previous research focused on non-neuronal cells and did not examine the effects of normal expression levels of AD-related proteins, leaving it unclear to what degree decreased endocytosis and other molecular movement within cells played a causative role.

Goldstein and colleagues analyzed neurons created from induced pluripotent stem cells in which they generated PS1 and APP mutations characteristic of fAD using the emerging genome editing technologies CRISPR and TALEN. In this “disease-in-a-dish” approach, they found that the mutated neurons displayed altered distribution and trafficking of APP and internalized lipoproteins (proteins that combine with or transport fat and other lipids in blood plasma). Specifically, there were elevated levels of APP in the soma or cell body while levels were reduced in the neuronal axons.

In previous work, Goldstein’s team had demonstrated that PS1 and APP mutations impaired the activity of specific cellular enzymes. In the latest work, they found that treating mutated fAD neurons with a beta-secretase inhibitor rescued both endocytosis and transcytosis (molecule movement within a cell) functions.

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Brain Cell ‘Executioner’ Identified

Despite their different triggers, the same molecular chain of events appears to be responsible for brain cell death from strokes, injuries and even such neurodegenerative diseases as Alzheimer’s. Now, researchers at Johns Hopkins say they have pinpointed the protein at the end of that chain of events, one that delivers the fatal strike by carving up a cell’s DNA. The find, they say, potentially opens up a new avenue for the development of drugs to prevent, stop or weaken the process.

A report on the research appears in the Oct. 7 issue of the journal Science.

The new experiments, conducted in laboratory-grown cells, build on earlier work by research partners Ted Dawson, M.D., Ph.D., now director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, and Valina Dawson, Ph.D., professor of neurology. Their research groups found that despite their very different causes and symptoms, injury, stroke, Alzheimer’s disease, Parkinson’s disease and the rare, fatal genetic disorder Huntington’s disease have a shared mechanism of a distinct form of “programmed” brain cell death they named parthanatos after the personification of death in Greek mythology and PARP, an enzyme involved in the process.

“I can’t overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury,” Ted Dawson says. His and Valina Dawson’s research groups have spent years delineating each of the links in the parthanatos chain of events and the roles of the proteins involved.

The current study, they say, has completed the chain. From previous studies, the researchers knew that when a protein called mitochondrial apoptosis-inducing factor, or AIF, leaves its usual place in the energy-producing mitochondria of the cell and moves to the nucleus, it sparks the carving up of the genome housed in the nucleus and leads to cell death.

But AIF itself, they say, can’t cut DNA. So then-postdoctoral fellow Yingfei Wang, Ph.D., now an assistant professor at the University of Texas Southwestern Medical Center, used a protein chip to screen thousands of human proteins to find those that interacted most strongly with AIF. Working with the 160 candidates she uncovered, she then used custom molecules called small interfering RNAs to stop each of those proteins’ manufacture, one by one, in lab-grown human cells to see if doing so would prevent cell death.

One of the 160 proteins, known as macrophage migration inhibitory factor (MIF), was a winner. “We found that AIF binds to MIF and carries it into the nucleus, where MIF chops up DNA,” Ted Dawson says. “We think that’s the final execution step in parthanatos.”

The group reports that in work to be published, it also identified a few chemical compounds that block MIF’s action in the lab-grown cells, protecting them from parthanatos. Dawson says they plan to test these in animals, and modify them to maximize their safety and effectiveness.

He cautions that while parthanatos is known to cause cell death in many brain conditions, MIF’s ability to chop up DNA has so far only been definitively linked with stroke — when the MIF gene was disabled in mice, the damage caused by a stroke was dramatically reduced. “We’re interested in finding out whether MIF is also involved in Parkinson’s, Alzheimer’s and other neurodegenerative diseases,” he says. If so, and if an inhibitor of MIF proves successful in testing, it could have implications for treating many conditions, he says.

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Iowa State University Scientists Identify New Lead In Search For Parkinson’s Cure

AMES, Iowa – Recently published research from Iowa State University may hint at a new treatment for Parkinson’s disease.

In a paper published in the academic journal Nature Communications, ISU scientists identified a protein called Prokineticin-2 (PK2) that may protect brain cells and is expressed with greater frequency in the early stages of Parkinson’s disease.

“The neurons use PK2 to cope with stress. It’s an in-built protective mechanism,” said Anumantha Kanthasamy, a Clarence Hartley Covault Distinguished Professor in veterinary medicine, the Eugene and Linda Lloyd Endowed Chair of Neurotoxicology, and chair of biomedical sciences at Iowa State. Kanthasamy, one of the paper’s lead authors, has been working to understand the complex mechanisms of Parkinson’s and searching for a cure for the past two decades.

Prokineticin-2 stimulates the neurons to produce more mitochondria, the part of the cell that produces energy. The resulting improved energy production helps neurons withstand the ravages of the disease, which is a neurological disorder that results in insufficient levels of dopamine in the brain.

Parkinson’s disease is a progressive disorder that takes years to develop. A better understanding of Prokineticin-2 could turn up a means of slowing development of the disease or lead to new therapies, Kanthasamy said. For instance, there may be ways to stimulate more production of the protein or protein analogs to bind with its receptors on neurons, he said.

The research team took a multidisciplinary and integrated approach to studying Parkinson’s disease. The study was funded by a grant from the National Institutes of Health to Kanthasamy and Arthi Kanthasamy, a professor of biomedical sciences and Anumantha’s spouse. Six graduate students in Kanthasamy’s lab also contributed to the study, including co-first authors Richard Gordon and Matthew Neal, as well as researchers at other institutions.

The scientists studied cultured brain cells, a rodent model and post-mortem human brains to track changes brought on by Parkinson’s disease, and they confirmed a high expression of Prokineticin-2 in each facet of the study.

It was this team effort that resulted in a comprehensive finding, Arthi Kanthasamy noted.

The discovery prompted the research team to investigate more thoroughly.

“Of the thousands and thousands of factors we tracked in our experiments, why was this protein expressed so highly?” Arthi Kanthasamy said.

Finding the answer to that question poses a challenge that will take time to overcome, but the potential appears to be significant, she said.

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New Clinical Trial Will Test Cancer Drug As Alzheimer’S Treatment

The Alzheimer’s Drug Discovery Foundation (ADDF) announces a $2.1 million grant awarded to R. Scott Turner, MD, PhD, of Georgetown University Medical Center to conduct a phase II clinical trial of low-dose nilotinib (marketed as Tasigna® for use as a cancer therapy) in patients with Alzheimer’s disease.

Nilotinib is an FDA-approved drug for the treatment of adult chronic myeloid leukemia. In preclinical studies conducted by Georgetown researchers, nilotinib reduced cognitive impairment by targeting two of the underlying causes of Alzheimer’s—neuroinflammation and misfolded proteins. Nilotinib triggers a process (called autophagy) that removes the toxic proteins tau and beta-amyloid from the brain before they accumulate into plaques and tangles.

Dr. Turner, co-medical director of Georgetown University Medical Center’s Translational Neurotherapeutics Program (TNP) and director of the Georgetown Memory Disorders Program, says, “By stimulating the brain’s normal autophagic process, which clears out these misfolded proteins in cells, we hope to prevent or slow the progression of Alzheimer’s. In fact, nilotinib may be a first—a broad-spectrum anti-neurodegenerative drug that targets all misfolded protein aggregates that accumulate in the brain of Alzheimer’s patients. By targeting both amyloid and tau, this study may point the way to a new strategy in Alzheimer’s disease treatment.”

The preclinical research was conducted by Charbel Moussa, MD, PhD, scientific and clinical research director for Georgetown’s TNP, who explains, “Nilotinib seems to activate the cell’s garbage disposal machine, reduce plaques and tangles and reverse cognitive decline in animal models of Alzheimer’s disease. We hope that this trial will clarify the effects of nilotinib in Alzheimer’s patients.” Moussa will be a co-investigator on the Alzheimer’s trial.

The trial is expected to start this year and will include 42 patients, with half randomized to receive an escalating dose of nilotinib, while the other half receives a placebo. The primary objectives of the study will be to test the drug’s safety and tolerability and to measure whether nilotinib reduces inflammation and the presence of beta-amyloid and tau in spinal fluid. Dr. Turner and his colleagues in the Georgetown Memory Disorders Program will also perform cognitive and functional abilities tests.

Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “The ADDF is proud to support a clinical trial that holds such promise for Alzheimer’s patients. This funding is part of our wider initiative to use the knowledge gained from cancer research to advance effective treatments for Alzheimer’s.”

The ADDF’s initiative “Learning from Cancer to Advance Treatments for Neurodegenerative Diseases” launched in 2015 with a conference held in partnership with the New York Academy of Sciences. Its goal is both to develop new therapies and test existing cancer therapies for their potential in treating Alzheimer’s disease. In addition to the nilotinib trial at Georgetown, this initiative includes funding for drug development projects at Oryzon Genomics, Rodin Therapeutics, and Yuma Therapeutics.

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Georgetown Receives FDA Clearance To Conduct Clinical Trial With Nilotinib In Alzheimer’s Disease

Georgetown University Medical Center (GUMC) today announces the U.S. Food and Drug Administration has completed its review of an investigational new drug application (IND) for the use of nilotinib in a phase II clinical trial for patients with mild to moderate Alzheimer’s disease.

The FDA also informed GUMC investigators that the study can proceed. The clinical trial is expected to begin this year at Georgetown University Medical Center with its clinical partner, MedStar Georgetown University Hospital.

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of nilotinib (sold as Tasigna®) on biomarkers and clinical outcomes in people with mild to moderate Alzheimer’s disease.

The rationale for using nilotinib is based on research conducted at Georgetown and involves clearing the brain of accumulated beta-amyloid (Abeta) plaques and Tau tangles. Both biomarkers are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear Tau and Abeta and other toxic proteins.

“In a 2015 small study at Georgetown, patients with Parkinson’s and dementia with Lewy bodies were given nilotinib. As my colleagues reported, all who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers — the same biomarkers seen in Alzheimer’s ,” explains Scott Turner, MD, PhD, co-medical director of Georgetown University Medical Center’s Translational Neurotherapeutics Program and director of the Georgetown Memory Disorders Program, who will lead the Alzheimer’s study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study gives an even stronger rationale.”

Charbel Moussa, MD, PhD, conducted the preclinical research that led to the discovery of nilotinib for the treatment of neurodegenerative diseases.

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Moussa, scientific and clinical research director for the Georgetown Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, nilotinib turns on autophagy for about four to eight hours — long enough to clean out the cells without causing cell death. Toxic proteins that build up again will be cleared when the drug is given again the next day.”

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Genetic ‘Switch’ Identified As Potential Target For Alzheimer’S Disease

A team at the MRC Clinical Sciences Centre (CSC), based at Imperial College London, has found an important part of the machinery that switches on a gene known to protect against Alzheimer’s Disease.

Working in collaboration with scientists at the Hong Kong University (HKU) and the Erasmus University in Rotterdam, CSC associate professor Richard Festenstein explored the steps by which this Neuroglobin gene is gradually switched on, or up-regulated.

Neuroglobin has previously been shown to protect against Alzheimer’s disease in mice in which it makes the protective Neuroglobin. It is thought that the gene might play a protective role early in the disease in patients, but appears to be down-regulated as the disease progresses. It may therefore prove useful in developing new ways to try to prevent or treat this common cause of dementia, for which there is currently no cure.

Professor Festenstein and Dr Tan-Un from HKU, with help from Professor Sjaak Phillipsen at the Erasmus University, examined how the Neuroglobin gene ‘folds up’ in the cell using a technique called chromosome conformation capture. In results published today in the journal Nucleic Acids Research, they showed that a particular region of DNA, outside the coding region of the Neuroglobin gene itself, loops round to make contact with the start of the gene.

They tested the ability of this newly-identified DNA region to switch on the Neuroglobin gene using two approaches. First, they linked the DNA region directly to another so-called ‘reporter’ gene, and demonstrated simply that it does indeed act as an up-regulator. Second, they used the new ‘Crispr’ technique of gene editing to completely remove this section of DNA from the cell, and showed that the Neuroglobin gene was no longer switched on.

Together, the results gave the team confidence that this newly-identified DNA region is indeed a powerful switching mechanism of the Neuroglobin gene.

As Neuroglobin is thought to be protective in Alzheimer’s, it may be possible in the future to use this ‘switch’ in developing new treatments, such as gene therapy. Such therapeutic approaches require a compact ‘chunk’ of DNA to be most efficient. Importantly, the team pinpointed the position of the new regulatory region, and found that it is some distance away from the Neuroglobin gene itself. It may now be possible to remove the less relevant sections of DNA in between the Neuroglobin gene and its regulator to create an efficient therapeutic gene therapy unit. It may be that this target may prove useful not only in Alzheimer’s but also in other neurodegenerative diseases.

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Study Discovers Potential New Target For Treatment Of Spinal Muscular Atrophy

For the first time, scientists found that in spinal muscular atrophy (SMA), the affected nerve cells that control muscle movement, or motor neurons, have defects in their mitochondria, which generate energy used by the cell. Impaired mitochondrial function and structure in motor neurons were discovered before symptoms occurred, suggesting a role in disease development.

These findings, published inHuman Molecular Genetics, point to new possibilities for targeted therapy for SMA.

“Restoring mitochondrial function might be a new treatment strategy for SMA,” said Yongchao Ma, PhD, senior author and Ann Marie and Francis Klocke, MD Research Scholar, Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago. He also is Assistant Professor of Pediatrics, Neurology and Physiology at Northwestern University Feinberg School of Medicine.
Infants born with SMA are not able to hold up their heads or sit up on their own, and they rarely survive beyond 2 years of age.

“While the genetic cause of this devastating disease has been identified, our study describes how mitochondrial dysfunction might contribute to motor neuron destruction even before the onset of symptoms,” said Ma. “Our findings provide new insights into SMA pathogenesis, which is crucial to developing new therapies.”

Ma and colleagues first discovered that mitochondria was involved in SMA when they analyzed gene expression profiles of motor neurons from SMA and control mice. They observed that the genes related to many mitochondrial functions were significantly dysregulated in SMA motor neurons.

“This discovery was unexpected and led us to test whether mitochondrial functions were changed in motor neurons from SMA mouse models,” said Ma.

Using sophisticated technology, the study found that mitochondria in SMA motor neurons produce energy at a slower rate, depleting the nerve. SMA mitochondria was less healthy, as evidenced by its decreased membrane potential. It also had increased oxidative stress level, which is toxic to the neuron. The movement of mitochondria was impaired as well, which would cause it to get stuck at the junction between nerve and muscle, leaking toxins and eventually disrupting the connection. Mitochondria in SMA motor neurons was also fragmented and swollen, which is consistent with the functional defects measured by the study.

“Motor neurons have high energy demands, which would make them highly sensitive to defects in their mitochondria,” says Ma. “These defects might lead to the symptom of motor neuron degeneration in SMA,” says Ma.

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Scalpel-Free Surgery Proves Safe, Effective for Treating Essential Tremor

A study published this week in the prestigious New England Journal of Medicine offers the most in-depth assessment yet of the safety and effectiveness of a high-tech alternative to brain surgery to treat the uncontrollable shaking caused by the most common movement disorder.

The paper outlines the results of an international clinical trial, led by Jeff Elias, MD, of the University of Virginia Health System, that evaluated the scalpel-free approach called focused ultrasound for the treatment of essential tremor (ET), a condition that afflicts an estimated 10 million Americans. Not only did the researchers determine that the procedure was safe and effective, they found that it offered a lasting benefit, reducing shaking for trial participants throughout the 12-month study period.

“This study represents a major advance for neurosurgery, treatment of brain disease and specifically the treatment of ET,” Elias said. “For the first time in a randomized controlled trial, we have shown that ultrasound can be precisely delivered through the intact human skull to treat a difficult neurological disease.”

Pioneering Tremor Trial
The multi-site clinical trial included 76 participants with moderate to severe essential tremor, a condition that often robs people of their ability to write, feed themselves and carry out their normal daily activities. The trial participants all had tried existing medications, without success. The mean age was 71, and most had suffered with their tremor for many years.

Seventy-five percent of participants received the experimental treatment using focused ultrasound guided by magnetic resonance imaging. The remaining 25 percent underwent a sham procedure, to act as the control group. (They would later be given the opportunity to undergo the real procedure.)

Participants who received the treatment showed dramatic improvement, with the beneficial effects continuing throughout the study period. The researchers employed a 32-point scale to assess tremor severity, and they found that mean tremor scores improved by 47 percent at three months and 40 percent at 12 months. Participants reported major improvements in their quality of life. People who couldn’t feed themselves soup or cereal could again do so.

Participants who received the sham procedure, on the other hand, showed no significant improvements.

“The degree of tremor control was very good overall in the study, but the most important aspects were the significant gains in disabilities and quality of life – that’s what patients really care about,” Elias said.

The most commonly reported side effects were gait disturbances and numbness in the hand or face; in most instances, these side effects were temporary but some were permanent.

FDA Approved
Based on the clinical trial led by Elias, the federal Food and Drug Administration has approved the focused ultrasound device, manufactured by InSightec Inc., for the treatment of essential tremor. The device focuses sound waves inside the brain to create heat, much like a magnifying glass focuses light. That heat can then be used to interrupt the troublesome brain connections responsible for the tremor. Elias can actually watch as patients’ tremor decreases, and the real-time imaging allows him to zone in on exactly the right spot before making any permanent changes to the brain.

The FDA approval means UVA can make the procedure available to eligible patients. UVA, however, is still working out the necessary logistics; it’s not yet clear when Elias will begin treating patients. Because the approach is so new, insurance plans will not yet cover the procedure, though that may change in the coming months. The cost at UVA has not yet been determined.

People interested in the procedure can learn more at uvahealth.com/focusedultrasound. The site includes a list of frequently asked questions and will be updated as UVA prepares to make the treatment available.

The procedure is not for everyone with essential tremor. It can’t be used in patients who cannot undergo MRI imaging, including those with implanted metallic devices such as a pacemaker. It is also not available for pregnant women, people with heart conditions or very high blood pressure, patients with kidney disease or clotting disorders, patients on blood thinners, patients with a history of strokes or brain tumors and people with substance abuse issues. There are other exclusions as well. Doctors at UVA will evaluate potential patients to determine their eligibility and then recommend the best course of treatment.

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Potential therapeutic target for Huntington’s disease

There is new hope in the fight against Huntington’s disease. Scientists at the Gladstone Institutes discovered that changing a specific part of the huntingtin protein prevented the loss of critical brain cells and protected against behavioral symptoms in a mouse model of the disease.

Huntington’s disease causes jerky, uncoordinated movements and a loss of control of motor function. It also results in deficits in learning and memory, as well as personality changes, such as dementia, depression, and aggression. Huntington’s is ultimately fatal, and there are no treatments to stop or slow its progression.

The disease is linked to a mutation in the Huntingtin gene, which causes a protein of the same name to fold up incorrectly like misshapen origami. Neurons cannot get rid of the misfolded protein, so it builds up in the brain, wreaking havoc in the cells.

In the new study, published in the Journal of Clinical Investigation, scientists in the laboratory of Steve Finkbeiner, MD, PhD, showed that modifying the huntingtin protein through a process called phosphorylation can actually make the protein less toxic and allows cells to eliminate it more easily. In fact, phosphorylating a specific spot on the protein called S421 protected a mouse model of Huntington’s from developing symptoms of the disease.

“I was shocked at the profound effect phosphorylation had on the Huntington’s model mice,” said first author Ian Kratter, MD, PhD, a former graduate student at Gladstone and the University of California, San Francisco (UCSF). “They showed few signs of the motor dysfunction, depression, or anxiety that are characteristic of the disease. In most of our tests, they were virtually indistinguishable from healthy mice.”

The mice were also protected against neuron death, particularly in the striatum, the movement and reward center of the brain that is first affected in Huntington’s disease. The scientists think that phosphorylation enables neurons to remove more of the harmful protein so it does not accumulate and damage the cell.

“Phosphorylation helps control how proteins fold and the systems in cells that clear proteins,” explained Finkbeiner, who is a senior investigator at Gladstone. “This is exciting, because a lot of the work we’ve done points to these protein removal pathways as being important not only for Huntington’s disease, but also for other neurodegenerative disorders. Understanding how phosphorylation links to these pathways could help treat several different brain diseases.”

The researchers are now exploring ways to mimic the effects of phosphorylation with a drug.

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Inosine treatment helps recovery of motor functions after brain injury

Brain tissue can die as the result of stroke, traumatic brain injury, or neurodegenerative disease. When the affected area includes the motor cortex, impairment of the fine motor control of the hand can result. In a new study published in Restorative Neurology and Neuroscience, researchers found that inosine, a naturally occurring purine nucleoside that is released by cells in response to metabolic stress, can help to restore motor control after brain injury.

Based on evidence from rodent studies, researchers used eight rhesus monkeys ranging in age from 5 to 10 years (approximately equivalent to humans from 15 to 30 years of age). All received medical examinations and motor skills were tested, including video recording of fine motor functions used to retrieve small food rewards. All monkeys were given initial MRI scans to ensure there were no hidden brain abnormalities.

Brain injuries were created in the area controlling each monkey’s favored hand. Four monkeys received inosine treatment, while four received a placebo. Research staff were not informed regarding which monkeys were included in the treatment vs placebo groups. Recovery of motor function was then measured for a period of 14 weeks after surgery.

While both the treated and placebo groups recovered significant function, three out of four of the treated monkeys were able to return to their pre-operative grasping methods. The placebo group developed a compensatory grasping method for retrieving food rewards unlike the original thumb-and-finger method.

“In the clinical context, the enhanced recovery of grasp pattern suggests that inosine facilitates greater recovery from this type of cortical injury and motor impairment,” explained lead investigator Tara L. Moore, PhD, of the Department of Anatomy & Neurobiology and the Department of Neurology, Boston University School of Medicine, Boston, MA, USA. “To our knowledge, this is the first study to demonstrate the positive effects of inosine for promoting recovery of function following cortical injury in a non-human primate.”

Inosine has also been administered in human clinical trials for multiple sclerosis and Parkinson’s disease and has been proven to be safe in doses up 3000 mg/day. Athletes have used inosine as a nutritional supplement for decades, and inosine supplements are widely available commercially. “Given the effectiveness of inosine in promoting cortical plasticity, axonal sprouting, and dendritic branching, the present evidence of efficacy after cortical injury in a non-human primate, combined with a long history of safe use, indicates a need for clinical trials with inosine after cortical injury and spinal cord injury,” noted Dr. Moore.

The study points to neural plasticity, whereby the brain essentially “re-wires” connections between neurons to reestablish control pathways, as a therapeutic target for the recovery of fine motor control and grasping ability. Further study of cortical tissue from these monkeys is currently being completed and may provide further insights into the mechanisms underlying recovery.

 

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Scientists keep a molecule from moving inside nerve cells to prevent cell death

Amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is a progressive disorder that devastates motor nerve cells. People diagnosed with ALS slowly lose the ability to control muscle movement, and are ultimately unable to speak, eat, move, or breathe. The cellular mechanisms behind ALS are also found in certain types of dementia.

A groundbreaking scientific study published in Nature Medicine has found one way an RNA binding protein may contribute to ALS disease progression. Cells make RNA to carry instructions for making proteins from DNA to protein-constructing machinery.

The culprit protein, TDP-43, normally binds to small pieces of newly read RNA and helps shuttle the fragments around inside nerve cell nuclei. The study describes for the first time the molecular consequences of misplaced TDP-43 inside nerve cells, and demonstrates that correcting its location can restore nerve cell function. Misplacement of TDP-43 in nerve cells is a hallmark of ALS and other neurological disorders including frontotemporal dementia (FTD), Alzheimer’s, Parkinson’s, and Huntington’s diseases. Studies that characterize common mechanisms behind these diseases could have widespread implications and may also accelerate development of broad-based therapies.

To find the misplaced TDP-43, the researchers viewed nerve cells donated by people who died from ALS or FTD under high powered microscopes. They discovered TDP-43 accumulates in nerve cell mitochondria, critical structures responsible for generating the enormous amount of energy nerve cells require. By physically isolating the affected mitochondria the researchers were able to pinpoint TDP-43’s exact location inside the subcellular structures. They were also able to characterize variations of the protein most likely to get misplaced.

This important work was led by Xinglong Wang, PhD, from the department of pathology at Case Western Reserve University School of Medicine and a team of scientists from his laboratory.

“By multiple approaches, we have identified the mitochondrial inner membrane facing matrix as the major site for mitochondrial TDP-43,” explained Wang. “Mitochondria might be major accumulation sites of TDP-43 in dying neurons in various major neurodegenerative diseases.”

The researchers discovered that once inside the mitochondria, TDP-43 resumes its RNA binding role and attaches itself to mitochondrial genetic material. This disrupts the mitochondria’s ability to generate energy for the cell. Wang’s team was able to precisely identify the RNA in mitochondria that was bound by TDP-43 and observe the resultant disassembly of mitochondrial protein complexes. This finding provides much needed clarity on the consequences of TDP-43 misplacement inside nerve cells and opens the door for deeper studies involving a range of neurological disorders. Although the study focused on ALS and FTD, according to Wang “mislocalization of TDP-43 represents a key pathological feature correlating strongly with symptoms in more than half of Alzheimer’s disease patients.”

Mutations in the gene encoding TDP-43 have long been linked to neurodegenerative diseases like ALS and FTD. Wang’s team found that disease-associated mutations in TDP-43 enhance its misplacement inside nerve cells. The researchers also identified sections of TDP-43 that are recognized by mitochondria and serve as signals to let it inside. These sections could serve as therapeutic targets, as the study found blocking them prevents TDP-43 from localizing inside mitochondria. Importantly, Wang’s team was able to keep TDP-43 out of nerve cell mitochondria in mice using small proteins which “almost completely” prevented nerve cell toxicity and disease progression.

“We, for the first time, provide the novel concept that the inhibition of TDP-43 mitochondrial localization is sufficient to prevent TDP-43-linked neurodegeneration,” said Wang. “Targeting mitochondrial TDP-43 could be a novel therapeutic approach for ALS, FTD and other TDP-43-linked neurodegenerative diseases.”

Wang has begun to develop small proteins that prevent TDP-43 from reaching mitochondria in human nerve cells, and has a patent pending for the therapeutic molecule used in the study.

There is no treatment currently available for ALS or FTD. The average life expectancy for people newly diagnosed with ALS is just three years, according to The ALS Association.