Potential New Autism Drug Shows Promise in Mice

Scientists have performed a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton’s fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children—roughly 2.4 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). The condition is now called MEF2C Haploinsufficiency Syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice—it’s a good example of why basic science is so important,” Lipton said.

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism,” Lipton said, “and in fact we already have preliminary evidence for this.”

For the study, the researchers created a laboratory model of MHS by engineering mice to have—like human children with MHS—just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests—in some cases restoring performance essentially to normal.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. “We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives,” said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton’s group is also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome—and NitroSynapsin appears to work in this ‘human context’ as well. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton’s research going forward.

In an amazing twist, the scientific team also found in Alzheimer’s disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve ‘network’ communication in the brain may eventually lead to its use in several neurological diseases.

Newly described process in Parkinson’s protein as a potential new therapy route

An international group of researchers led by Professor Wim Versées (VIB-VUB) has unraveled the workings of an essential mechanism in ‘Parkinson’s protein’ LRRK2. Their study demonstrates a direct link between the protein’s ‘dimerization’ – two copies that are bound together -and mutations that lead to Parkinson’s disease. This process could eventually lead to a promising therapy route. This research has been published in the leading academic journal Nature Communications.

Approximately 4 million people worldwide currently suffer from Parkinson’s disease, and this number is only expected to increase. The most frequent genetic causes of the illness are mutations in the gene responsible for controlling the production of protein LRRK2, which includes two enzymes: a kinase and a GTPase. Because this kinase is at the root of neuronal problems, kinase inhibitors have already been clinically tested. However, these inhibitors eventually cause lung and kidney problems, making it imperative for scientists to seek alternative solutions.

Parkinson’s protein comes in a single or doubled state

In close collaboration with Prof. Arjan Kortholt (University of Groningen), the team of Prof. Wim Versées (VIB-VUB) sought a better understanding of LRRK2’s complex structure. It is already known that the kinase portion of the protein is active in the protein’s ‘dimeric’ or ‘double’ state, which involves two identical copies of the protein bound together. Using this information as a starting point, the team investigated how this binding is established. To do so, the scientists observed similar proteins occurring in certain bacteria.

Prof. Wim Versées (VIB-VUB): “The GTPase enzyme, a component of LRRK2, regulates the state of the entire protein. In doing so, it determines whether a LRRK2 protein is in its inactive ‘single’ state, or its active ‘double’ state. In addition, we saw a clear link between the protein dimerization and genetic mutations in Parkinson’s disease. As a result, this regulation process bconstitutes an attractive new target for future drug development.”

Prof. Arjan Kortholt (Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen): “Our study is a milestone in the long-term scientific discussion covering the dimeric state of LRRK2 and its link with Parkinson’s. But although this is a significant step forward, it will be quite some time before we understand all the details enough to manipulate the process.”

Note: Wim Versées is part of the lab of Jan Steyaert of the VIB-VUB Center for Structural Biology

Better ‘Mini Brains’ Could Help Scientists Identify Treatments for Zika-Related Brain Damage

UCLA researchers develop improved technique for creating brain tissue from stem cells

UCLA researchers have developed an improved technique for creating simplified human brain tissue from stem cells. Because these so-called “mini brain organoids” mimic human brains in how they grow and develop, they’re vital to studying complex neurological diseases.

In a study published in the journal Cell Reports, the researchers used the organoids to better understand how Zika infects and damages fetal brain tissue, which enabled them to identify drugs that could prevent the virus’s damaging effects.

The research, led by senior author Ben Novitch, could lead to new ways to study human neurological and neurodevelopmental disorders, such as epilepsy, autism and schizophrenia.

“Diseases that affect the brain and nervous system are among the most debilitating medical conditions,” said Novitch, UCLA’s Ethel Scheibel Professor of Neurobiology and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Mini brain organoids provide us with opportunities to examine features of the human brain that are not present in other models, and we anticipate that their similarity to the real human brain will enable us to test how various drugs impact abnormal or diseased brain tissue in far greater detail.”

For about five years, scientists have been using human pluripotent stem cells, which can create any cell type in the body, to develop mini brain organoids. But the organoids they produced have generally been difficult to use for research because they had highly variable structures and inconsistent cellular composition, and because they didn’t correctly mimic the layered structure of the brain and were too small — often no bigger than the head of a pin. They also didn’t survive very long in the laboratory and contained neural tissue that was difficult to classify in relation to real human brain tissue.

The organoids developed by Novitch’s group have a stratified structure that accurately mimics the human brain’s onion-like layers, they survive longer and have a larger and more uniform shape.

To create the brain organoids, Novitch and his team made several modifications to the methods that other scientists used previously: The UCLA investigators used a specific number of stem cells and specialized petri dishes with a modified chemical environment; previous methods used varying amounts of cells and a different type of dish. And they added a growth factor called LIF, which stimulated a cell-signaling pathway that is critical for human brain growth.

The researchers found critical similarities between the organoids they developed and real human brain tissue. Among them: The organoids’ anatomy closely resembled that of the human cortex, the region of the brain associated with thought, speech and decision making; and a diverse array of neural cell types commonly found in the cortex were all present in the organoids, and they exhibited electrical activities and network function, meaning they were capable of communicating with one another much like the neural networks in the human brain do.

The UCLA scientists also found that they could modify their methodology to make other parts of the brain including the basal ganglia, which are involved in the control of movement and are affected by neurodegenerative conditions such as Parkinson’s disease and Huntington’s disease.

“While our organoids are in no way close to being fully functional human brains, they mimic the human brain structure much more consistently than other models,” said Momoko Watanabe, a UCLA postdoctoral fellow and the study’s first author. “Other scientists can use our methods to improve brain research because the data will be more accurate and consistent from experiment to experiment and more comparable to the real human brain.”

When the team exposed the organoids to Zika, they discovered specifically how the virus destroys neural stem cells, the cells from which the brain grows during fetal development. Novitch’s team found that there are four specific molecules, called receptors, on the outer surface of neural stem cells; previous studies have indicated that the Zika virus could bind to these receptors and infect the cells. The researchers then mapped the changes that occur in the neural stem cells after Zika infection, presenting a clearer picture of how the virus infiltrates and harms fetal brain tissue.

Zika is associated with an unusually high incidence of fetal brain damage, so understanding how neural stem cells are affected by the virus could be an important new step toward a treatment.

The researchers tested several drugs on the Zika-infected organoids. They found three that are effective at blocking the virus’s entry into the brain tissue, including two that protected neural stem cells by preventing the interaction between the virus and entry receptors on the neural stem cells. In previous studies by Novitch and other UCLA colleagues, one of those drugs reduced brain damage in fetal mice infected with Zika.

“Many neurological diseases or conditions arise from defects in the way one neuron communicates with another or from the way an external factor, such as a virus, interacts with neural cells,” Novitch said. “If we can focus in at the level of cellular communication, we should be able to model those undesirable cellular interactions and counteract them with drugs or other therapies.”

The team plans to continue using its improved organoids to better understand human brain development and to learn more about autism spectrum disorders, epilepsy and other neurological conditions.

The experimental drugs used in the preclinical study have not been tested in humans or approved by the Food and Drug Administration for treating Zika in humans.

Gene Identified That May Provide Potential Therapy for Cerebral Cavernous Malformations

Researchers at University of California San Diego School of Medicine, with national collaborators, have identified a series of molecular clues to understanding the formation of cerebral cavernous malformations (CCMs). The study offers the first genome-wide analysis of the transcriptome of brain microvascular endothelial cells after KRIT1 inactivation. Findings were published September 28 in the Journal of Experimental Medicine.

“These mouse studies reveal a critical mechanism in the pathogenesis of cerebral cavernous malformations and point to the possibility of using angiogenesis inhibitors, such as TSP1 for potential therapy,” said Mark H. Ginsberg, MD, professor of medicine, UC San Diego School of Medicine.

CCMs are collections of enlarged and irregular blood vessels in the central nervous system (CNS), for which there is no drug therapy. The vessels are prone to leakage causing headaches, seizures, paralysis, hearing or vision loss, or bleeding in the brain. There are two forms of the condition: familial and sporadic, affecting 1 in 200 patients in the U.S. The current treatment for CCMs involves invasive surgery, however, surgery is not possible for all patients due to location of vascular lesions within the CNS.

The most common cause of familial cavernous malformations is mutations of KRIT1. The protein produced from this gene is found in the junctions connecting neighboring blood vessel cells. Loss of function mutations in KRIT1 result in weakened contacts between blood vessel cells and CNS vascular abnormalities as seen in CCMs.

“Inactivation of KRIT1 in endothelial cells causes a cascade of changes in the expression of genes that regulate cardiovascular development,” said Ginsberg. “What we learned is that reduced expression of a protein encoded by one of these genes, TSP1, contributes to the growth of CCMs. Loss of one or two copies of THBS1, the gene that encodes TSP1, makes a mouse model of the disease much worse. Conversely, administration of 3TSR, a fragment of TSP1, reduces lesions in this mouse model. This means that replacement of TSP1 by 3TSR or other angiogenesis inhibitors may be a preventative for CCMs or treatment of the disease.”

Biologists Find New Source for Brain’s Development

A team of biologists has found an unexpected source for the brain’s development, a finding that offers new insights into the building of the nervous system.

The research, which appears in the journal Science, discovered that glia, a collection of non-neuronal cells that had long been regarded as passive support cells, in fact are vital to nerve-cell development in the brain.

“The results lead us to revise the often neuro-centric view of brain development to now appreciate the contributions for non-neuronal cells such as glia,” explains Vilaiwan Fernandes, a postdoctoral fellow in New York University’s Department of Biology and the study’s lead author. “Indeed, our study found that fundamental questions in brain development with regard to the timing, identity, and coordination of nerve cell birth can only be understood when the glial contribution is accounted for.”

The brain is made up of two broad cell types, nerve cells or neurons and glia, which are non-nerve cells that make up more than half the volume of the brain. Neurobiologists have tended to focus on the former because these are the cells that form networks that process information.

However, given the preponderance of glia in the brain’s cellular make-up, the NYU researchers hypothesized that they could play a fundamental part in brain development.

To explore this, they examined the visual system of the fruit fly. The species serves as a powerful model organism for this line of study because its visual system, like the one in humans, holds repeated mini-circuits that detect and process light over the entire visual field.

This dynamic is of particular interest to scientists because, as the brain develops, it must coordinate the increase of neurons in the retina with other neurons in distant regions of the brain.

In their study, the NYU researchers found that the coordination of nerve-cell development is achieved through a population of glia, which relay cues from the retina to the brain to make cells in the brain become nerve cells.

“By acting as a signaling intermediary, glia exert precise control over not only when and where a neuron is born, but also the type of neuron it will develop into,” notes NYU Biology Professor Claude Desplan, the paper’s senior author.

The research was supported, in part, by a grant from the National Institutes of Health (EY13012).

Courtesy of Vilaiwan M. Fernandes, Desplan Lab, NYU’s Department of Biology.

Stabilizing TREM2 — a potential strategy to combat Alzheimer’s disease

A gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.

Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research, published today in EMBO Molecular Medicine, sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.

Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material.

TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK.

Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.

As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. “Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease,” said Crowther.

While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. “The end result is the same. In both cases, there is too little full-length TREM protein on microglia,” said Haass. “This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy.”

Data Showing Anti-Addictive/Pain Relief Benefits of Cannabinoids to be Presented at Upcoming Society of Neuroscience Meeting

Data recently obtained from Nemus Bioscience‘s research and development partner, the University of Mississippi (UM) will show the superiority of the NEMUS proprietary analogue of CBD, NB2222, versus plant-derived CBD in ameliorating pain in a validated mouse (murine) model of chemotherapy-induced peripheral neuropathy using an opioid as an active comparator.  The data was accepted for a presentation at the 2017 Annual Meeting of the Society of Neuroscience to held in Washington, D.C. on November 11th-15th.

Additional data will also detail the anti-addictive potential of NB2222 in an animal model of opioid addiction. The in vivo research was led by Professor Kenneth Sufka of the University of Mississippi based on the molecular cannabinoid discovery work performed by the team at ElSohly Laboratories, Inc. (ELI) in collaboration with the University, spearheaded by Dr. Mahmoud ElSohly, who also holds a faculty appointment at the University.

“NEMUS has previously reported that our proprietary analogue of CBD, NB2222, has exhibited a competitive bioavailability profile when compared to plant-derived CBD, penetrating the blood-brain barrier to enter the central nervous system, as well as all major organs, especially the liver, in animal studies conducted to-date,” commented Brian Murphy, MD, MBA, the NEMUS CEO and Chief Medical Officer. “The data being presented by Dr. Sufka is a pivotal start to developing the analogue of CBD to potentially address medical indications in multiple organ systems, especially the eye, brain and diseases of the liver.”

Dr. Kenneth Sufka, professor of Psychology and Pharmacology and Research Professor with the National Center for Natural Products Research at UM stated, “We have been able to demonstrate that NB2222 was able to deliver analgesia comparable to morphine, which has been implicated in the current global opioid abuse epidemic. The research team then moved to the next step using a validated animal model of addiction to opioids to assess the anti-abuse potential of NB2222 as a therapeutic. We look forward to presenting the data this fall.”

“The discovery team is very pleased with the performance of this analogue of CBD in the studies that have been performed so far,” reported Dr. Mahmoud ElSohly, professor at the National Center for Natural Products Research at the University of Mississippi School of Pharmacy and co-inventor of the CBD analogue. “We believe that bio-engineered cannabinoids offer a unique opportunity to potentially enhance the efficacy and safety profile of this class of therapeutics. We look forward to working with NEMUS in advancing other cannabinoid-based therapies across a spectrum of diseases.”

Dr. Murphy noted, “It appears that NB2222 could have a number of uses beyond pain management and ocular conditions, and moving forward, Nemus will consider strategic collaborations for this CBD analogue.”

Lysosomes in Healthy Neurons and in Neurons with Juvenile Batten Disease

Researchers at Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and King’s College London have discovered a treatment that improves the neurological symptoms in a mouse model of juvenile Batten disease. This discovery brings hope to patients and families affected by the disease that a treatment might be available in the future. The study appears in Nature Communications.

“Patients with juvenile Batten disease are born healthy and reach the expected developmental milestones of the first 4 to 6 years of age,” said senior author Dr. Marco Sardiello, assistant professor of molecular and human genetics at Baylor. “Then, these children progressively regress their developmental achievements; they gradually lose their vision and develop intellectual and motor disabilities, changes in behavior and speech difficulties. Most people with this condition live into their 20s or 30s. This inherited, rare disease has no cure or treatment other than palliative care.”

“As we started this project, patients and families affected by this condition visited us in the laboratory,” said first author Dr. Michela Palmieri, who was a postdoctoral fellow in the Sardiello lab during this project and currently is at the San Raffaele Scientific Institute in Milan, Italy. “We were deeply affected by our interactions with the patients and their families and this further motivated us to pursue this research with the hope that maybe one day it will lead to a treatment that will improve the lives of people affected by this condition.”

Juvenile Batten disease, a problem with cellular waste management

Like a large dynamic city, a cell carries out many activities that generate waste. Waste needs to be disposed of properly in order for the city to continue its activities without interruption. If waste management fails, waste progressively accumulates and eventually leads to interruption and paralysis of the activities of the city. Something similar happens in cells when cellular waste is not discarded.

The lysosomes are the structures in charge of clearing the waste produced by the cell’s regular functions. Lysosomes are sacs inside all cells containing enzymes that degrade cellular waste into its constituent components, which the cell can recycle or discard. When lysosomes fail and cellular waste accumulates, disease follows. Although all types of cells can be affected by defects in lysosomal waste processing and cellular waste accumulation, brain cells – neurons – are particularly susceptible.

“In juvenile Batten disease, one of nearly 50 human lysosomal storage disorders, the function of brain cells is progressively affected by the accumulation of cellular waste,” Sardiello said. “This accumulation leads to perturbation of many cellular processes, cell death and progressive regression of motor, physical and intellectual abilities.”

A novel approach to finding a treatment

“A few years back we discovered a protein in cells called TFEB, a master transcription factor that stimulates the cell to produce more lysosomes and degrade cellular waste more effectively,” said Sardiello. “So we thought about counteracting the accumulation of cellular waste in Batten disease by acting on TFEB.”

“We and others had found that enhancing the activity of TFEB genetically can help counter the accumulation of cellular waste in different diseases,” Sardiello said. “What was missing was a way to activate TFEB with a drug that in the future could be put in a pill to treat the condition. We focused on investigating how to activate TFEB pharmacologically.”

“We discovered that TFEB is under the control of another molecule called Akt, which is a kinase, a protein that can modify other proteins,” said Palmieri. “Akt has been studied in detail. There are drugs available that can modulate the activity of Akt.”

The researchers discovered that Akt modifies TFEB by adding a chemical group, a phosphate, to it. This chemical modification inactivates TFEB.

“We wanted to inhibit Akt to keep TFEB more active,” said Palmieri. “We discovered that the sugar trehalose is able to do this job.”

Testing a treatment for juvenile Batten disease in a mouse model of the condition

The scientists tested the effect of trehalose in a mouse model of juvenile Batten disease.

“We dissolved trehalose in drinking water and gave it to mice that model juvenile Batten disease,” said Sardiello. “Then, over time we examined the mice’s brain cells under the microscope. We found that the continuous administration of trehalose inhibits Akt and activates TFEB in the brains of the mice. More active TFEB meant more lysosomes in the brain and increased lysosomal activity, followed by decreased accumulation of the storage material and reduced tissue inflammation, which is one of the main features of this disease in people, and reduced neurodegeneration. These changes resulted in the mice living significantly longer. This is a good start toward finding a treatment for people with this disease.”

“We are very excited that these findings put research a step closer to understanding the mechanisms that underlie human lysosomal storage diseases,” said Palmieri. “We hope that our research will help us design treatments to counteract this and other human diseases with a pathological storage component, such as Alzheimer’s, Huntington’s and Parkinson’s diseases, and hopefully ameliorate the symptoms or reduce the progression of the disease for those affected.”

Scientists Engineer Gene Pathway to Grow Brain Organoids with Surface Folding

One of the most significant ways in which the human brain is unique is the size and structure of the cerebral cortex. But what drives the growth of the human cortex, likely the foundation for our unique intellectual abilities?

In research published in the journal Cell Stem Cell—in a study entitled, Induction of expansion and folding in human cerebral organoids—researchers at Whitehead Institute provide insight into a specific gene pathway that appears to regulate the growth, structure, and organization of the human cortex. They also demonstrate that 3D human cerebral organoids—miniature, lab-grown versions of specific brain structures—can be effective in modeling the molecular, cellular, and anatomical processes of human brain development. And they suggest a new path for identifying the cells affected by Zika virus.

“We found that increased proliferation of neural progenitor cells (NPs) induces expansion of cortical tissue and cortical folding in human cerebral organoids,” says Yun Li, a lead author of study and post-doctoral researcher at Whitehead Institute. “Further, we determined that deleting the PTEN gene allows increased growth factor signaling in the cell, unleashing its growth potential, and stimulating proliferation.”

These findings lend support to the notion that an increase in the proliferative potential of NPs contributes to the expansion of the human cerebral neocortex, and the emergence of surface folding.

With normal NPs, the human organoid developed into relatively small cell clusters with smooth surface appearance, displaying some features of very early development of a human cortex. However, deleting PTEN allowed the progenitor population to continue expanding and delayed their differentiation into specific kinds of neurons—both key features of the developing human cortex. “Because the PTEN mutant NPs experienced more rounds of division and retained their progenitor state for an extended period, the organoids grew significantly larger and had substantially folded cortical tissue,” explains Julien Muffat, also a lead author and post-doctoral researcher at Whitehead Institute.

In contrast, they found that while PTEN deletion in mouse cells does create a somewhat larger than normal organoid, it does not lead to significant NP expansion or to folding. “Previous studies have suggested that abnormal variation in PTEN expression may play an important role in driving brain development conditions leading to syndromes such as Autism Spectrum Disorders,” says Rudolf Jaenisch, Founding Member of Whitehead Institute and senior author of the study. “Our findings suggest that the PTEN pathway is also an important mechanism for controlling brain-structure differences observed between species.”

The Whitehead investigators chose to focus on the PTEN gene because it had previously been shown to have some function in cortical development and to have a role in regulating progenitor cells of various lineages. Notably PTEN loss-of-function mutations have been associated with human macrocephaly.

In this study, deletion of the PTEN gene increased activation of the PI3K-AKT pathway and thereby enhanced AKT activity in the human NPs comprising the 3D human cerebral organoids; it promoted cell cycle re-entry and transiently delayed neuronal differentiation, resulting in a marked expansion of the radial glia and intermediate progenitor population. Validating the molecular mechanism at work with PTEN, the investigators used pharmacological AKT inhibitors to reverse the effect of the PTEN deletion. They also found that they could regulate the degree of expansion and folding by tuning the strength of AKT signaling—with reduced signaling resulting in smaller and smooth organoids, and increased signaling producing larger and more folded organoids.

Finally, the researchers utilized the 3D human cerebral organoid system to show that infection with Zika virus impairs cortical growth and folding. In the organoids, Zika infection at the onset of surface folding (day 19 of development) led to widespread apoptosis; and, ten days later, it had severely hampered organoid growth and surface folding. Zika infection of 4-week-old organoids, showed that PTEN mutant organoids were much more susceptible to infection than normal control organoids; notably, they showed increased apoptosis and decreased proliferation of progenitor cells.

“Although not an original goal of our study, we have demonstrated that 3D human cortical organoids can be very effective for Zika modeling—better enabling researchers to observe how human brain tissue reacts to the infection and to test potential treatments,” Li says.

Researchers Find Potential Therapy For Brain Swelling During Concussion

Biomedical engineering researchers pre-treated cells that swell after traumatic injury with an existing, FDA-approved drug.

A team of biomedical engineering researchers at the University of Arkansas have identified a cause of fluid swelling of the brain, or cellular edema, that occurs during a concussion.

The researchers discovered that pre-treating the cells with an existing, FDA-approved drug used for epilepsy and altitude sickness reduces the expression of a specific protein that causes swelling.

Their findings were published in a recent issue of Nature’s Scientific Reports.

“Our study found that mild traumatic brain injury resulted in increased expression of a protein called aquaporin-4, which caused a massive cellular influx of fluid, leading to increased astrocyte cell volume and injury,” said Kartik Balachandran, assistant professor of biomedical engineering. “We then worked with a drug called Acetazolamide. Our results showed that Acetazolamide minimized cell swelling and injury, suggesting a therapeutic role for this drug in reducing the detrimental effects of concussions.”

In addition to Balachandran, who led the study, the research was conducted by Nasya Sturdivant, biomedical-engineering doctoral candidate; Jeffrey Wolchok, assistant professor of biomedical engineering; and partners at the FDA’s National Center for Toxicological Research in Jefferson, Arkansas.

Mild traumatic brain injury, also known as a concussion, is a devastating condition that is commonly experienced in car accidents, full-contact sports and battlefield injuries. One of the main factors that leads to the high death rate in patients who experience mild traumatic brain injury is the swelling or edema of astrocytes, the most abundant cell type in the brain.

The researchers engineered a benchtop bioreactor to examine astrocyte cells. This device helped them see that mild traumatic brain injury led to an increased expression of aquaporin-4, the protein that causes a large cellular influx of fluid, which in turn leads to increased astrocyte cell volume.

“This study demonstrates the collaborative neuro-engineering efforts that are contributing to both diagnostic and therapeutic methods for addressing traumatic brain injury,” said Raj Rao, professor and chair of the Department of Biomedical Engineering at the University of Arkansas.

New Study Finds Cardiac PET/CT Imaging Effective In Detecting Calcium Blockages, Assessing Heart Attack Risk

Many people who experience chest pain but don’t have a heart attack breathe a big sigh of relief when a stress test comes back negative for blockages in their blood vessels.

But a new study by cardiac researchers at the Intermountain Medical Center Heart Institute in Salt Lake City found they may not be off the hook after all.

Researchers studied 658 men and women between the ages of 57 and 77 who passed a stress test for blocked arteries and who were later found to have calcium in their arteries after being screened by imaging technology that measured their total coronary artery calcification.

They found that five percent of patients who passed their stress test and later tested high for calcium in their arteries — 31 of 658 patients — went on to have an adverse cardiac event within one year. Such events included death, heart attack and stroke.
Researchers say there is something more doctors can do to assess a patient’s risk of future heart attack: check the calcium — a sign of plaque buildup — in a patient’s arteries.

“We now have the ability to better measure coronary artery calcification,” says Viet Le, MPAS, PA-C, lead author of the Intermountain Medical Center Heart Institute study, who will deliver results at the American Heart Association Scientific Session in New Orleans on Nov 14, at 10:45 am, CST.

“People say, ‘I’m good. They gave me a stress test,’” said Le. “But it doesn’t tell the whole story. The story it tells is that on that day your engine — your heart — passed the test. Some of these people die within a year from a heart attack.”
Cardiac experts have known for years that calcium left by plaque is a good marker of heart disease, but there was not good imaging technology to measure it without exposing the patient to too much radiation, Le said. That changed about five years ago.
PET/CT, an advanced nuclear imaging technology that combines positron emission tomography (PET) and computed tomography (CT) in one machine, allows physicians doing a chemical stress test to also measure coronary artery calcification.

Calcification cannot be reversed, but the plaque that causes it can be reduced or stabilized with proper medication, diet and exercise.

Researchers found that 33 patients in the study, or five percent, had no or mild calcification, and they had no cardiac events. But there was a significant correlation between the amount of calcium and the occurrence of cardiac events in the remainder of the patients.

Twelve of 309 (3.88 percent) patients with moderate calcification had a cardiac event within a year, 10 of 190 (5.26 percent) with severe calcification had a cardiac event within a year, and nine of 126 (7.14 percent) with very severe calcification had a cardiac event within a year. In total, 16.28 percent of calcified patients in the study had a heart event.

The results confirmed for Le the value of assessing calcification in patients suspected of having clogged arteries.

“Right now, it’s a neglected tool that should better be utilized,” he said.

Temple Attains $20 Million Award For Materials, Brain Injury Research

In one of the largest cooperative agreements for research in Temple University history, an interdisciplinary team of faculty is participating in a $20 million, two-year agreement with other universities and the U.S. Army Research Laboratory, or ARL.

Temple will be working with the ARL to perform research in three major areas: understanding and improving the performance of materials through the use of computational modeling; understanding the mechanisms and thresholds of traumatic brain injury by reviewing clinical, behavioral and biochemical changes related to traumatic brain injuries and concussions; and exploring new ways to improve protection against ballistics impacts.

“This pioneering research by some our most highly regarded faculty supports the protection of soldiers and also has potential for broader applications,” said Temple University President Richard M. Englert. “Temple’s research enterprise is clearly on the rise, and this is a tremendous example of what our expertise can do to improve lives.”

Other higher education collaborators include the University of Southern California, University of Southern Mississippi and the University of North Texas.

“ARL is creating a transformative global science and technology ecosystem by linking government, academia and business to share the best and brightest people, ideas and facilities in forward-reaching research areas of strategic importance to the Army,” said Philip Perconti, ARL acting director.

Under the leadership of Vice President for Research Michele M. Masucci, Temple’s research team features: College of Science and Technology Dean and Laura H. Carnell Professor of Science Michael L. Klein; Laura H. Carnell Professor of Physics and Chemistry John Perdew; Associate Professor of Neuroscience and Neurovirology T. Dianne Langford of Temple’s Lewis Katz School of Medicine; and Associate Professor of Kinesiology Ryan Tierney in the College of Public Health. Langford and Tierney’s project team includes additional Temple faculty from medicine, engineering, science and technology, and public health, as well as a representative from Temple Athletics.

“This award evidences that by working together across schools, colleges and universities, Temple’s faculty is able to provide national leadership in the design, development and measurement of advanced materials to protect army personnel as well as athletes,” Masucci said. “Through improving our knowledge of the protective effects of such materials by conducting clinical studies of their use, we hope to dramatically improve the safety of individuals at risk for traumatic brain injury.”

The research effort, which aims to create a new class of materials for use in personal protective equipment and decrease brain injuries, will leverage Temple’s Center for Computational Design of Functional Layered Materials and the Temple Materials Institute to develop and test new materials, as well as the university’s clinical, research and educational expertise in monitoring and understanding the consequences of head injuries.

“The project will also develop technologies that can be commercialized and brought to market, broadening the benefits of the program to society at large,” said Stephen Nappi, Temple’s associate vice president for technology commercialization and business development.

Restoring The Sense Of Touch In Amputees Using Natural Signals Of The Nervous System

Scientists at the University of Chicago and Case Western Reserve University have found a way to produce realistic sensations of touch in two human amputees by directly stimulating the nervous system.

The study, published Oct. 26 in Science Translational Medicine (STM), confirms earlier research on how the nervous system encodes the intensity, or magnitude, of sensations. It is the second of two groundbreaking publications this month by University of Chicago neuroscientist Sliman Bensmaia, PhD, using neuroprosthetic devices to recreate the sense of touch for amputee or quadriplegic patients with a “biomimetic” approach that approximates the natural, intact nervous system.

On Oct. 13, in a separate publication from STM, Bensmaia and a team led by Robert Gaunt, PhD, from the University of Pittsburgh, announced that for the first time, a paralyzed human patient was able to experience the sense of touch through a robotic arm that he controls with his brain. In that study, researchers interfaced directly with the patient’s brain, through an electrode array implanted in the areas of the brain responsible for hand movements and for touch, which allowed the man to both move the robotic arm and feel objects through it.

The new study takes a similar approach in amputees, working with two male subjects who each lost an arm after traumatic injuries. In this case, both subjects were implanted with neural interfaces, devices embedded with electrodes that were attached to the median, ulnar and radial nerves of the arm. Those are the same nerves that would carry signals from the hand were it still intact.

“If you want to create a dexterous hand for use in an amputee or a quadriplegic patient, you need to not only be able to move it, but have sensory feedback from it,” said Bensmaia, who is an associate professor of organismal biology and anatomy at the University of Chicago. “To do this, we first need to look at how the intact hand and the intact nervous system encodes this information, and then, to the extent that we can, try to mimic that in a neuroprosthesis.”

Recreating different sensations of intensity

The latest research is a joint effort by Bensmaia and Dustin Tyler, PhD, the Kent H. Smith Professor of Biomedical Engineering at Case Western Reserve University, who works with a large team trying to make bionic hands clinically viable. Tyler’s team, led by doctoral student Emily Graczyk, systematically tested the subjects’ ability to distinguish the magnitude of the sensations evoked when their nerves were stimulated through the interface. They varied aspects of the signals, such as frequency and intensity of each electrical pulse. The goal was to understand if there was a systematic way to manipulate the sensory magnitude.

Earlier research from Bensmaia’s lab predicted how the nervous system discerns intensity of touch, for example, how hard an object is pressing against the skin. That work suggested that the number of times certain nerve fibers fire in response to a given stimulus, known as the population spike rate, determines the perceived intensity of a given stimulus.

Results from the new study verify this hypothesis: A single feature of electrical stimulation—dubbed the activation charge rate—was found to determine the strength of the sensation. By changing the activation charge rate, the team could change sensory magnitude in a highly predictable way. The team then showed that the activation charge rate was also closely related to the evoked population spike rate.

Building neuroprosthetics that approximate the natural nervous system

While the new study furthers the development of neural interfaces for neuroprosthetics, artificial touch will only be as good as the devices providing input. In a separate paper published earlier this year in IEEE Transactions on Haptics, Bensmaia and his team tested the sensory abilities of a robotic fingertip equipped with touch sensors.

Using the same behavioral techniques that are used to test human sensory abilities, Bensmaia’s team, led by Benoit Delhaye and Erik Schluter, tested the finger’s ability to distinguish different touch locations, different pressure levels, the direction and speed of surfaces moving across it and the identity of textures scanned across it. The robotic finger (with the help of machine learning algorithms) proved to be almost as good as a human at most of these sensory tasks. By combining such high-quality input with the algorithms and data Bensmaia and Tyler produced in the other study, researchers can begin building neuroprosthetics that approximate natural sensations of touch.

Without realistic, natural-feeling sensations, neuroprosthetics will never come close to achieving the dexterity of our native hands. To illustrate the importance of touch, Bensmaia referred to a piano. Playing the piano requires a delicate touch, and an accomplished pianist knows how softly or forcefully to strike the keys based on sensory signals from the fingertips. Without these signals, the sounds the piano would make would not be very musical.

“The idea is that if we can reproduce those signals exactly, the amputee won’t have to think about it, he can just interact with objects naturally and automatically. Results from this study constitute a first step towards conveying finely graded information about contact pressure,” Bensmaia said.

Neighborhoods Important Factor In Risk Of Stroke For All Races

A higher neighborhood advantage, or socioeconomic status, of where a person lives contributes to a lower risk of having a stroke no matter the person’s race, according to findings published in the Oct. 14 online issue of Neurology®, the medical journal of the American Academy of Neurology.

The report from the University of Alabama at Birmingham REasons for Geographic And Racial Differences in Stroke study shows this effect is the same for black and white adults, both men and women.

“More blacks than whites in the United States have strokes and die from strokes,” saidVirginia Howard, Ph.D., lead author of the study and professor in the UAB School of Public Health Department of Epidemiology. “More people who live in the Southeastern area known as the stroke belt have stroke and die from stroke compared to those who live in the rest of the United States.”

This study showed that residents in more disadvantaged neighborhoods had greater stroke risk than those who lived in more advantaged neighborhoods. The neighborhood index is composed of six factors, including a higher value of housing units and higher proportion of residents employed in professional occupations. A higher score in all of these categories leads to a higher advantaged neighborhood.

The observation was true even after adjustment for age, race, sex and region of the country. But after adjustment for other stroke risk factors, there was no association between the level of the neighborhood advantage and stroke risk, suggesting that those living in more disadvantaged neighborhoods are more likely to develop risk factors including hypertension, diabetes and smoking. Because of being more likely to develop these risk factors, they are at higher risk of stroke.

“These results are consistent with other evidence showing that factors associated with living in more disadvantaged neighborhoods contribute to stroke risk. However, it is difficult to separate the influence of neighborhood characteristics from characteristics of the individuals living in the neighborhood,” Howard said. “Many social and behavioral risk factors, such as smoking and physical inactivity, are more prevalent in the less advantaged neighborhoods. Greater attention needs to be paid to risk factor management strategies in disadvantaged neighborhoods in order to make a difference in preventing stroke on an individual level.”

The current study looked at measures of the neighborhood advantage where people live to determine whether these factors contributed to future stroke risk. Data came from the REGARDS study, a national random sample of the general population with more people selected from the stroke belt and about half black, half white.

The study involved 24,875 people with an average age of 65 who had not had a stroke at the start of the study. The participants were divided into four neighborhood groups, ranging from lowest level of advantage to the highest. The participants were followed for an average of seven and a half years. During that time, 929 people had a stroke.

This study has advantages over other studies in that it includes individuals of low, middle, upper-middle and high individual wealth across 1,833 urban and rural counties in the United States, and a large number of both blacks and whites. Other stroke risk factors were measured prior to the stroke.

New Hope For Recovery Of Hand Movement For Stroke Patients

Stroke patients are starting a trial of a new electronic device to recover movement and control of their hand.

Neuroscientists at Newcastle University have developed the device, the size of a mobile phone, which delivers a series of small electrical shocks followed by an audible click to strengthen brain and spinal connections.

The experts believe this could revolutionise treatment for patients, providing a wearable solution to the effects of stroke.

Following successful work in primates and healthy human subjects, the Newcastle University team are now working with colleagues at the prestigious Institute of Neurosciences, Kolkata, India, to start the clinical trial. Involving 150 stroke patients, the aim of the study is to see whether it leads to improved hand and arm control.

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.”

Recovering hand control

Publishing today in the Journal of Neuroscience, the team report on the development of the miniaturised device and its success in healthy patients at strengthening connections in the reticulospinal tract, one of the signal pathways between the brain and spinal cord.

This is important for patients as when people have a stroke they often lose the major pathway found in all mammals connecting the brain to spinal cord. The team’s previous work in primates showed that after a stroke they can adapt and use a different, more primitive pathway, the reticulospinal tract, to recover.

However, their recovery tends to be imbalanced with more connections made to flexors, the muscles that close the hand, than extensors, those that open the hand. This imbalance is also seen in stroke patients as typically, even after a period of recuperation, they find that they still have weakness of the extensor muscles preventing them opening their fist which leads to the distinctive curled hand.

Partial paralysis of the arms, typically on just one side, is common after stroke, and can affect someone’s ability to wash, dress or feed themselves. Only about 15% of stroke patients spontaneously recover the use of their hand and arm, with many people left facing the rest of their lives with a severe level of disability.

Senior author of the paper, Professor Baker added: “We have developed a miniaturised device which delivers an audible click followed by a weak electric shock to the arm muscle to strengthen the brain’s connections. This means the stroke patients in the trial are wearing an earpiece and a pad on the arm, each linked by wires to the device so that the click and shock can be continually delivered to them.

“We think that if they wear this for 4 hours a day we will be able to see a permanent improvement in their extensor muscle connections which will help them gain control on their hand.”

Improving connections

The techniques to strengthen brain connections using paired stimuli are well documented, but until now this has needed bulky equipment, with a mains electric supply.

The research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates. In the paper they report how they pair a click in a headphone with an electric shock to a muscle to induce the changes in connections either strengthening or weakening reflexes depending on the sequence selected. They demonstrated that wearing the portable electronic device for seven hours strengthened the signal pathway in more than half of the subjects (15 out of 25).

Professor Stuart Baker added: “We would never have thought of using audible clicks unless we had the recordings from primates to show us that this might work. Furthermore, it is our earlier work in primates which shows that the connections we are changing are definitely involved in stroke recovery.”

The work has been funded through a Milstein Award from the Medical Research Council and the Wellcome Trust.

The clinical trial is just starting at the Institute of Neurosciences, Kolkata, India. The country has a higher rate of stroke than Western countries which can affect people at a younger age meaning there is a large number of patients. The Institute has strong collaborative links with Newcastle University enabling a carefully controlled clinical trial with results expected at the end of this year.

Brain Cancer And Leukemia: New Molecular Mechanisms Decoded

Brain cancer and leukemia are two potentially fatal diseases that affect thousands of Canadians each year. But a joint study conducted by researchers Frederick Antoine Mallette, of the Maisonneuve-Rosemont Hospital Research Centre and the University of Montreal, and Marc-Étienne Huot, of Laval University, and published in the prestigious scientific journal Nature Communications has uncovered new molecular causes of brain cancer and leukemia.

We already knew the existence of a mutation phenomenon involving certain metabolic enzymes called isocitrate dehydrogenases 1 and 2 (IDH1/2) in various forms of brain cancer, including gliomas and glioblastomas, and in acute myeloid leukemia. Although the mutated forms of IDH1/2 appear to contribute to cancer formation, until now we had only limited understanding of the ways in which these metabolic defects caused cancer. Research conducted by Mélissa Carbonneau, a master’s student in Professor Mallette’s laboratory, has helped to better understand the effect of IDH1/2 mutations in cancer by demonstrating their role in activating the pathways involved in cell proliferation and survival.

“With the identification of the molecular modes of action that contribute to cancer in patients carrying IDH1/2 mutations, it is now possible to consider personalized treatment to potentially improve therapeutic response,” said Dr. Mallette.
Some statistics

It is estimated that in 2015, 3,000 Canadians were diagnosed with brain and spinal cord cancer, and 6,200 Canadians were diagnosed with leukemia.

Visual Cortex Plays Role In Plasticity Of Eye Movement Reflex

By peering into the eyes of mice and tracking their ocular movements, researchers made an unexpected discovery: the visual cortex – a region of the brain known to process sensory information – plays a key role in promoting the plasticity of innate, spontaneous eye movements. The study, published in Nature, was led by researchers at the University of California, San Diego (UCSD) and the University of California, San Francisco (UCSF) and funded by the National Eye Institute (NEI), part of the National Institutes of Health.

“This study elegantly shows how analysis of eye movement sheds more light on brain plasticity– an ability that is at the core of the brain’s capacity to adapt and function. More specifically, it shows how the visual cortex continues to surprise and to awe,” said Houmam Araj, Ph.D., a program director at the NEI.

Without our being aware of it, our eyes are in constant motion. As we rotate our heads and as the world around us moves, two ocular reflexes kick in to offset this movement and stabilize images projected onto our retinas, the light-sensitive tissue at the back of our eyes. The optokinetic reflex causes eyes to drift horizontally from side-to-side— for example, as we watch the scenery through a window of a moving train. The vestibulo-ocular reflex adjusts our eye position to offset head movements. Both reflexes are crucial to survival. These mechanisms allow us to see traffic while driving down a bumpy road, or a hawk in flight to see a mouse scurrying for cover.

The two reflexes occur automatically as a result of signals from the brainstem, an evolutionarily older part of the brain. These reflexes also are precisely coordinated in relation to each other. When one of the two reflexes is impaired by age or alcohol, for example, the other compensates. This orchestration requires adaptive plasticity, said the study’s lead investigator, Massimo Scanziani, Ph.D., who at the time of the study was professor of neurobiology at UCSD before moving to UCSF. Scanziani collaborated with the study’s first author, Bao-hua Liu, Ph.D., a post-doc at UCSD and Andrew Huberman, Ph.D., now associate professor at Stanford University.

Scanziani and his colleagues sought to understand the origins of this adaptive plasticity by studying the eye movements in mice before and after disabling their vestibular ocular reflex. In their mouse model, disabling the vestibulo-ocular reflex increases the optokinetic reflex. They measure the increase by holding the mouse’s head still and then presenting the mouse with visual stimuli in the form of black and white horizontal stripes that rotate around the mouse. A camera records the animal’s eye movements. More forceful eye movements indicate an increase in optokinetic reflex activity.

To test the visual cortex’s role in the plasticity of these reflexes, the researchers applied a technique called optogenetics, which uses light to turn target cells on or off. The researchers targeted inhibitory neurons in the visual cortex to turn them “on,” thus silencing that region of the brain. Silencing the visual cortex led to a significant reduction in the activity of the optokinetic reflex, suggesting that it is the visual cortex that is involved in mediating the plasticity between the optokinetic and the vestibulo-ocular reflexes.

Next, the researchers sought to learn more about how the visual cortex modulates the reflexes. It has long been observed that a collection of neural projections from the visual cortex extends to cells of the brainstem that regulate innate motor behaviors. The scientists lesioned these projections and again observed a decrease in the optokinetic reflex. Such findings suggest that the neural projections are the anatomical structures by which the visual cortex adjusts the plasticity of the optokinetic reflex, Scanziani said.

The findings shed new light on the role of the mammalian cortex in orchestrating eye movement, according to Scanziani. “Most of our reflexes are encoded in the brainstem, but from an evolutionary standpoint, the ability for one’s cortex to modify these reflexes expands one’s behavioral repertoire as the circumstances require,” he said. “If you’ve ever noticed how people in an audience tend to cough after a solo musical performance ends, you’ve seen this ability to modify reflexes in action. It’s an ability that appears to have been an attribute important for survival. After all when you’re hiding from a tiger, it would be the very worst moment to cough.”

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.

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.

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.