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Appendix identified as a potential starting point for Parkinson's disease

Removing the appendix early in life reduces the risk of developing Parkinson’s disease by 19 to 25 percent, according to the largest and most comprehensive study of its kind, published today in Science Translational Medicine.

The findings also solidify the role of the gut and immune system in the genesis of the disease, and reveal that the appendix acts as a major reservoir for abnormally folded alpha-synuclein proteins, which are closely linked to Parkinson’s onset and progression.

“Our results point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies that leverage the gastrointestinal tract’s role in the development of the disease,” said Viviane Labrie, Ph.D., an assistant professor at Van Andel Research Institute (VARI) and senior author of the study. “Despite having a reputation as largely unnecessary, the appendix actually plays a major part in our immune systems, in regulating the makeup of our gut bacteria and now, as shown by our work, in Parkinson’s disease.”

The reduced risk for Parkinson’s was only apparent when the appendix and the alpha-synuclein contained within it were removed early in life, years before the onset of Parkinson’s, suggesting that the appendix may be involved in disease initiation. Removal of the appendix after the disease process starts, however, had no effect on disease progression.

In a general population, people who had an appendectomy were 19 percent less likely to develop Parkinson’s. This effect was magnified in people who live in rural areas, with appendectomies resulting in a 25 percent reduction in disease risk. Parkinson’s often is more prevalent in rural populations, a trend that has been associated with increased exposure to pesticides.

The study also demonstrated that appendectomy can delay disease progression in people who go on to develop Parkinson’s, pushing back diagnosis by an average of 3.6 years. Because there are no definitive tests for Parkinson’s, people often are diagnosed after motor symptoms such as tremor or rigidity arise. By then, the disease typically is quite advanced, with significant damage to the area of the brain that regulates voluntary movement.

Conversely, appendectomies had no apparent benefit in people whose disease was linked to genetic mutations passed down through their families, a group that comprises fewer than 10 percent of cases.

“Our findings today add a new layer to our understanding of this incredibly complex disease,” said Bryan Killinger, Ph.D., the study’s first author and a postdoctoral fellow in Labrie’s laboratory. “We have shown that the appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins, which are implicated in Parkinson’s disease. This knowledge will be invaluable as we explore new prevention and treatment strategies.”

Labrie and her team also found clumps of alpha-synuclein in the appendixes of healthy people of all ages as well as people with Parkinson’s, raising new questions about the mechanisms that give rise to the disease and propel its progression. Clumped alpha-synuclein is considered to be a key hallmark of Parkinson’s; previously, it was thought to only be present in people with the disease.

“We were surprised that pathogenic forms of alpha-synuclein were so pervasive in the appendixes of people both with and without Parkinson’s. It appears that these aggregates — although toxic when in the brain — are quite normal when in the appendix. This clearly suggests their presence alone cannot be the cause of the disease,” Labrie said. “Parkinson’s is relatively rare — less than 1 percent of the population — so there has to be some other mechanism or confluence of events that allows the appendix to affect Parkinson’s risk. That’s what we plan to look at next; which factor or factors tip the scale in favor of Parkinson’s?”

Data for the study were gleaned from an in-depth characterization and visualization of alpha-synuclein forms in the appendix, which bore a remarkable resemblance to those found in the Parkinson’s disease brain, as well as analyses of two large health-record databases. The first dataset was garnered from the Swedish National Patient Registry, a one-of-a-kind database that contains de-identified medical diagnoses and surgical histories for the Swedish population beginning in 1964, and Statistics Sweden, a Swedish governmental agency responsible for official national statistics. The team at VARI collaborated with researchers at Lund University, Sweden, to comb through records for 1,698,000 people followed up to 52 years, a total of nearly 92 million person-years. The second dataset was from the Parkinson’s Progression Marker Initiative (PPMI), which includes details about patient diagnosis, age of onset, demographics and genetic information.

In all, this study involved scientists from Van Andel Research Institute, Northwestern University, Lund University and Michigan State University. In addition to Labrie and Killinger, authors include Zachary Madaj, M.S., Alec J. Haas, Yamini Vepa, Patrik Brundin, M.D., Ph.D., and Lena Brundin, M.D., Ph.D., of VARI; Jacek W. Sikora, Ph.D., and Paul M. Thomas, Ph.D., of the Proteomics Center of Excellence at Northwestern University; Nolwen Rey, Ph.D., of Paris-Saclay Institute of Neuroscience; Daniel Lindqvist, M.D., Ph.D., of Lund University; and Honglei Chen, M.D., Ph.D., of Michigan State University.

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Nanostraws deliver molecules to human cells safely and efficiently

Researchers can design the perfect molecule to edit a gene, treat cancer or guide the development of a stem cell, but none of that will matter in the end if they can’t get their molecules into the human cells they want to manipulate. The solution to that problem, described in a study published October 31 in Science Advances, could be miniscule nanostraws, tiny glass-like protrusions which poke equally tiny holes in cell walls to deliver their cargo.

A team led by Nicholas Melosh, an associate professor of materials science and engineering, first began testing nanostraws about five years ago using relatively tough cell lines derived from cancers, mouse cells and other sources. Now, Melosh and colleagues have shown the technique works in human cells as well, a result that could speed up medical and biological research and could one day improve gene therapy for diseases of the eyes, immune system or cancers.

“What you’re seeing is a huge push for gene therapy and cancer immunotherapy,” said Melosh, who is also a member of Stanford Bio-X, Stanford ChEM-H and the Wu Tsai Neurosciences Institute, but existing techniques are not up the challenge of delivering materials to all the relevant human cell types, especially immune cells. “They’re really tough compared to almost all other cells that we’ve handled,” he said.

Crossing the cell membrane

The idea of transporting chemicals across the cell membrane and into the cell itself is not new, but there are a number of problems with the methods scientists have until now relied on. In one common method, called electroporation, researchers use an electric current to open up holes in cell walls through which molecules such as DNA or proteins can diffuse through, but the method is imprecise and can kill many of the cells researchers are trying to work with.

In another method, researchers use viruses to carry the molecule of interest across a cell wall, but the virus itself carries risks. While there are similar methods that replace viruses with more benign chemicals, they are less precise and effective.

That was the state of affairs until just five or six years ago, when Melosh and colleagues came up with a new way of getting molecules into cells, based on Melosh’s expertise in nano materials. They would use electroporation, but do it in a vastly more precise way with nanostraws, which because of their relatively long, narrow profile help concentrate electric currents into a very small space.

At the time, they tested that technique on animal cells sitting atop a bed of nanostraws. When they turned on an electric current, the nanostraws opened tiny, regularly sized pores in the cell membrane — enough that molecules can get in, but not enough to do serious damage.

The electric current served another purpose as well. Rather than waiting for molecules to randomly float through the newly opened pores, the current drew molecules straight in to the cell, increasing the speed and precision of the process. The question at that time was whether the technique would be as effective on the kinds of human cells clinicians would need to manipulate to treat diseases.

Faster, Safer, More Precise

In the new paper, Melosh and team showed that the answer was yes — they successfully delivered molecules into three human cell types as well as mouse brain cells, all of which had proved difficult to work with in the past.

What’s more, the method was more precise, faster and safer than other methods. The nanostraw technique took just 20 seconds to deliver molecules to cells, compared with days for some methods, and killed fewer than ten percent of cells, a vast improvement over standard electroporation.

Melosh and his lab are now working to test the nanostraw method in some of the hardest to work with cells around, human immune cells. If they succeed, it could be a big step not just for scientists who want to modify cells for research purposes, but also for medical doctors looking to treat cancer with immunotherapy, which right now involves modifying a person’s immune cells using viral methods. Nanostraws would not only avoid that hazard but could potentially speed up the immunotherapy process and reduce its cost, as well, Melosh said.

Melosh is also an associate professor of photon science. Additional Stanford authors include Richard Lewis, a professor of molecular and cellular physiology, Joseph Wu, the Simon H. Stertzer, M.D., Professor and a professor of radiology, postdoctoral fellow Ruoyi Qiu, and graduate students Yuhong Cao and Angela Zhang.

The research was funded by grants from the National Institutes of Health, the National Science Foundation, the Knut and Alice Wallenberg Foundation and the Wu Tsai Neurosciences Institute.

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'Game-changing' skin sensor could improve life for a million hydrocephalus patients

Most people simply take ibuprofen when they get a headache. But for someone with hydrocephalus — a potentially life-threatening condition in which excess fluid builds up in the brain — a headache can indicate a serious problem that can result in a hospital visit, thousands of dollars in scans, radiation and sometimes surgery.

A new wireless, Band-Aid-like sensor developed at Northwestern University could revolutionize the way patients manage hydrocephalus and potentially save the U.S. health care system millions of dollars. The current standard of care involves the surgical implantation of a tube known as a ‘shunt’ to drain this excess fluid out of the brain. Shunts have a nearly 100 percent failure rate over 10 years, and diagnosing shunt failure is notoriously difficult.

A Northwestern Medicine clinical study successfully tested the device, known as a wearable shunt monitor, on five adult patients with hydrocephalus. The findings will be published Oct. 31 in Science Translational Medicine.

Device could change the lives of a million patients

A device like this would be life changing for Willie Meyer, 26, who has undergone 190 surgeries, spent virtually every holiday in the emergency room and almost missed his high school graduation because of emergency brain surgeries.

“I’m trying to live a normal life, and I really can’t because of the headaches,” Meyer said.

Hydrocephalus affects one in 1,000 live births and is about as common as Down Syndrome. Treating the condition costs an estimated $50,000 per patient per year, and costs the U.S. health care system about $1 billion per year. If left untreated, hydrocephalus can lead to death.

To treat the condition, surgeons implant a straw-like catheter, or shunt, into the brain to drain the excess fluid to another part of the body. More than 1 million Americans live with shunts and the constant threat of their failure.

When a shunt fails, the patient can experience headaches, nausea and low energy. A patient experiencing any of these symptoms must visit a hospital because if their symptoms are caused by a malfunctioning shunt, they could be life threatening. Once at the hospital, the patient must get a CT scan or an MRI and sometimes must undergo surgery to see if the shunt is working properly.

The groundbreaking new sensor, developed by the Rogers Research Group at Northwestern, allowed patients in the study to determine within five minutes of placing it on their skin if fluid was flowing through their shunt. The soft and flexible sensor uses measurements of temperature and heat transfer to non-invasively tell if and how much fluid is flowing through.

“We envision you could do this while you’re sitting in the waiting room waiting to see the doctor,” said co-lead author Siddharth Krishnan, a fifth-year Ph.D. student in the Rogers Research Group. “A nurse could come and place it on you and five minutes later, you have a measurement.”

‘A Band-Aid talking to a cellphone’

A very small rechargeable battery is built into the sensor. The device is Bluetooth enabled so it can talk to a smartphone and deliver the readings via an Android app.

“At the end of the day, from a patient perspective, it looks like a Band-Aid that’s talking to their cellphone,” said co-senior author John A. Rogers.

“It’s a wearable device with a specific but useful mode of operation that’s addressing an unmet need in clinical medicine,” said Rogers, the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery in the McCormick School of Engineering and a professor of neurological surgery at Northwestern University Feinberg School of Medicine. “There’s nothing like this out there today.”

Next steps: Clinical pediatric trial and moving beyond the lab

A larger pediatric clinical trial will be starting soon at Ann & Robert H. Lurie Children’s Hospital of Chicago with the goal of targeting this very vulnerable population. The study authors are also working on outsourced production on the scale of a few hundred sensors to support this study and further develop the technology.

“We realized this couldn’t be one of those research projects that stopped with the paper,” Krishnan said. “The last few months have been about taking this lab-scale prototype that we’ve essentially built by hand and thinking about how to make that something that can be manufactured externally with the same level of performance.”

That would be a relieve for Willie Meyer’s mother, Beth Meyer. She said she learned Willie had hydrocephalus when he was two years old after complaining that “his hair hurt.” He was too young to know how to vocalize his headache, which is common among pediatric hydrocephalus patients and is a source of stress for their caregivers.

“Shunt malfunction symptoms, like headaches or sleepiness, are things kids can have for lots of reasons, like the flu,” said co-senior author Dr. Matthew Potts, assistant professor of neurological surgery at Feinberg and a Northwestern Medicine physician. “So if a child has these symptoms, it’s very hard to know, and every time your kid says they have a headache or feels a little sleepy, you automatically think, ‘Is this the shunt?’ We believe that this device can spare patients a lot of the danger and costs of this process.”

When Willie was younger, Beth said they needed to bring along copies of his CT scans when they traveled, and would research local neurosurgeons in the area in case Willie got a headache.

“The biggest part of hydrocephalus is the unpredictability and not being able to know from one day to the next whether you’ll be in the emergency room or at home,” Beth said. “This type of device would get rid of the uncertainty.”

Co-lead author Dr. Amit Ayer, a sixth-year neurosurgery resident at Northwestern Medicine and an MBA student at Kellogg School of Management at Northwestern, has treated Willie’s hydrocephalus for the last four years. Ayer said his patients are a driving force behind his motivation to get the device to market.

“Our patients want to know when they can actually use the device and be part of the trial,” Ayer said. “I want to get it out there, so we can help make their lives better.”

Hydrocephalus can affect adults and children. Often the child is born with with the condition, whereas in adults, it can be acquired from some trauma-related injury, such as bleeding inside the brain or a brain tumor, Potts said.

Given the uncertainty and failure rates associated with shunts, the technology could create immense savings and improve the quality of life for nearly a million people in the U.S. alone.

The science behind the device

The sensor advances concepts in skin-like “epidermal electronics,” which the Rogers Research Group has been working on for nearly a decade.

The sensor uses a thermal transport measurement, which means the sensor uses tiny amounts of thermal power to minimally increase the temperature of the skin. If the shunt is working and the excess cerebral spinal fluid is draining properly, the sensor will measure a characteristic heat signature. Similarly, if there is no flow because the shunt has malfunctioned, the sensor will be able to quickly indicate that through heat flow measurements.

The team tested the device in the laboratory before heading to the clinic to perform a pilot study on five patients at Northwestern Memorial Hospital. The team could detect clear differences in cases between measurements over working shunts and on adjacent confusing control locations with no flow.

“This means if someone wants to check if their shunt is working, say, when they have a headache, they can quickly do what we call a ‘spot measurement,'” said co-lead author Dr. Tyler Ray, a postdoctoral research fellow in the Rogers Research Group. “This device can also measure flow throughout the day enabling, for the first time, the possibility of continuously monitoring shunt performance. This can lead to important insights into the dynamics of cerebral spinal fluid flow previously inaccessible with current diagnostic tools and flow measurement techniques.”

This study was funded by the Center for Bio-Integrated Electronics at Northwestern with small additional funding through the Dixon Translational Grant at Feinberg.

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Changes to RNA aid the process of learning and memory

RNA carries pieces of instructions encoded in DNA to coordinate the production of proteins that will carry out the work to be done in a cell. But the process isn’t always straightforward. Chemical modifications to DNA or RNA can alter the way genes are expressed without changing the actual genetic sequences. These epigenetic or epitranscriptome changes can affect many biological processes such as immune system response, nervous system development, various human cancers and even obesity.

Most of these changes happen through methylation, a process in which chemical molecules called methyl groups are added to a DNA or RNA molecule. Proteins that add a methyl group are known as “writers,” and proteins that can remove the methyl groups are “erasers.” For the methylation to have a biological effect, there must be “reader” proteins that can identify the change and bind to it.

The most common modification on messenger RNA in mammals is called N6-methyladenosine (m6A). It is widespread in the nervous system. It helps coordinate several neural functions, working through reader proteins in the YTH family of proteins.

In a new study published in Nature, scientists from the University of Chicago show how Ythdf1, a member of the YTH family that specifically recognizes m6A, plays an important role in the process of learning and memory formation. Using CRISPR/Cas9 gene editing tools to knock out Ythdf1in mice, they demonstrated how it promotes translation of m6A-modified messenger RNA (mRNA) in response to learning activities and direct nerve cell stimulus.

“This study opens the door to our future understanding of learning and memory,” said Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry, Biochemistry and Molecular Biology at UChicago and one of the senior authors of the study. “We saw differences in long-term memory and learning between the normal and knockout mice, demonstrating that the m6A methylation plays a critical role through Ythdf1.”

In 2015, He published a study in Cell showing how Ythdf1 recognizes m6A-modified mRNAs and promotes their translation to proteins. The new study further demonstrates how this translation increases specifically in response to nervous system stimulation.

Hailing Shi, a graduate student in He’s lab, led the new study, working with colleagues from Shanghai Tech University in China and the University of Pennsylvania. Mice express more Ythdf1 mRNAs in the hippocampus, part of the brain crucial to spatial learning and memory. So, the researchers conducted several experiments with both normal mice and mice without Ythdf1 to test the effects on their ability to learn from experiences.

In one scenario called the Morris water maze to test spatial memory, they used a water tank with a submerged platform a mouse could stand on to avoid swimming. Mice got several tries to learn where the platforms were located based on visual cues in a testing room. Then the platform was removed. The normal mice did a better job remembering where the platform used to be than the knockout mice.

The researchers also tested contextual and auditory fear memory in the different groups of mice by administering electrical shocks in combination with certain sounds in specific settings. Again, the normal mice demonstrated better contextual memory than knockout mice. They showed a fear response after being placed in the same setting again without the associated sounds, but not after hearing the sounds in a different setting.

The memory and learning deficits were reversible, however. When the researchers injected knockout mice with a virus carrying Ythdf1, their performance on memory and learning tasks improved dramatically.

The researchers also tested the response of cultured mouse neurons directly in the lab. When the normal cells were stimulated, they increased new protein production, compared to much less activity in Ythdf1 knockout cells.

“It’s really an exciting finding to show how the protein can respond to a neuronal stimulus which could contribute to controlled translation,” Shi said.

“It’s a stimulation-dependent upregulation of translation,” He added. “It makes sense because you don’t want to fire up your neurons constantly, only when you have a stimulation.”

While the current study identifies one important function for YTHDF1, there may be many other functions involved with other biological processes.

“This is not just limited to learning and memory. This stimulation induced translation should apply to many other systems,” He said. “The same m6A modification is known to play a role in the immune system when there is an infection, or when a cell moves to a different part of the body. So, I think this is a general concept.”

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Decoding how brain circuits control behavior

The mouse brain contains roughly 80 million neurons, all packed into a space about the size of a hazelnut. Those cells come in a vast assortment of shapes and sizes, and their connections with one another number in the billions — at least.

The brain depends on this circuitry to interpret information about the world, learn from experiences, and control movements. Nerve cells are intermingled in this tight space to form an intricate network — making it difficult for scientists to understand which cells are responsible for which tasks.

Now, in two papers published October 31, 2018, in the journal Nature, researchers at the Howard Hughes Medical Institute’s Janelia Research Campus and the Allen Institute for Brain Science have worked out how two types of intermingled nerve cells divide the labor to plan and initiate movements. By integrating cell-by-cell analyses of neurons’ shapes, gene activity, and function, the team has teased out which brain cells are responsible for these distinct but closely related jobs.

Combining such extensive analyses represents a major technical feat, says Janelia Group Leader Karel Svoboda. It’s a new approach to understanding brain function, he says. The work required multiple teams of scientists at multiple institutes teaming up to solve a single problem. Svoboda thinks that this kind of approach will be necessary to help researchers crack the most complex questions in neuroscience.

“Major progress in brain research will increasingly rely on these types of collaborations,” he says.

Charting new neural territory

Around the world, researchers have embarked on efforts to build comprehensive neural maps to uncover truths about the brain.

Neuroscientists are exploring the brain’s elaborate networks from many different angles, charting cell structures, molecular features, and neural activities. Combining this disparate information to gain insights about brain function remains an outstanding challenge, Svoboda says.

At Janelia, one long-term mapping effort involves neuronal anatomy. Scientists on the MouseLight project team have been determining the precise structure of neurons in the mouse brain — a massive undertaking that involves painstakingly tracing individual neurons’ wiry paths across thousands of images of the brain. Complementary efforts at the Allen Institute are charting cells’ gene expression, revealing key similarities and differences between cells and offering hints into cellular function.

In the new work, Janelia scientists Mike Economo, Sarada Viswanathan, Loren Looger, Svoboda, and colleagues joined forces with Allen Institute scientists to create complete gene expression profiles of cells within the mouse neocortex. The neocortex is the largest part of the mammalian brain responsible for higher cognitive functions. The team focused on the anterior lateral motor cortex (ALM), an area involved in planning and executing movements.

The Janelia and Allen Institute groups have been collaborating for years, Svoboda says. His lab has worked to describe how ALM neurons code information and control movements, and Allen Institute scientists used new single-cell RNA sequencing technology to analyze the molecular make-up of individual ALM neurons.

Bosiljka Tasic, Hongkui Zeng, and colleagues at the Allen Institute determined the full set of RNA molecules — the transcriptome — present in each of 23,822 neurons from the neocortex. This generated a complete picture of which genes were switched on in every cell — about 9,000 genes per cell, on average. Within the vast dataset, the researchers identified more than 130 groups of cells that shared transcriptomes.

Role definition

Next, the team correlated their molecular findings with structural information obtained through Janelia’s MouseLight project.

The scientists focused on large neurons in the ALM that carry information away from the cortex. Within this subset of neurons, two groups of cells defined by their transcriptomes also shared anatomic features. Their paths to other parts of the brain are distinct, the team discovered. One set connects to the brainstem, where motor neurons that direct the body to carry out actions reside. The second set connects with the thalamus, a sort of central switchboard in the brain.

Collectively, these cells have already received attention from neuroscientists because they are particularly vulnerable to neurodegenerative disease. “But it really hasn’t been appreciated that these neurons come in discrete flavors and might play different roles,” says Economo, a postdoctoral researcher in Svoboda’s lab.

To tease apart those roles, Economo targeted each cell class individually, manipulating and measuring activity as mice carried out a simple task — moving in a particular direction at a particular time. One group of neurons, those that connect the ALM to the thalamus, are crucial for planning future movements, the experiments revealed. The other set of neurons, those that connect the ALM to the brainstem, are required to initiate movement. Simply put, the two types of neurons fall into two classes and have distinct behaviors, Svoboda says. “These cell types carry different messages to different brain regions to produce different functions.”

By pulling together multiple data streams, he says, the team was able to bring clarity to a complex circuit question.

“Scientists can always find ways to divide cells into groups,” Tasic adds, but in this case, the groups offer a clear picture of each cell type’s role in shaping movement. It’s a key step in picking apart the complexity of the cortex.

With the functions of more than 100 molecularly defined cell types in the visual cortex and the ALM alone still to be explored, scientists have a lot of complexity left to unravel, Svoboda says.

But, he adds, with new research tools in development and large-scale mapping efforts accelerating, this type of neural decoding could soon be ramping up.

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Unique type of skeletal stem cells found in 'resting zone' are actually hard at work

Skeletal stem cells are valuable because it’s thought they can heal many types of bone injury, but they’re difficult to find because researchers don’t know exactly what they look like or where they live.

Researchers at the University of Michigan have identified a type of skeletal stem cell in the “resting zone” of the epiphyseal growth plate, which is a special cartilaginous tissue and an important driver for bone growth.

Noriaki Ono, U-M assistant professor of dentistry, said that locating skeletal stem cells in the resting zone makes sense because it’s widely believed that stem cells stay quiet until they’re needed.

To find the cells, Noriaki and colleagues used fluorescent proteins to mark specific groups of cells in mice and tracked the fate of these cells over time. In this way, they learned how the cells behaved in native conditions throughout the life-cycle, rather than on a petri dish, Noriaki said.

The cells they found met the criteria for skeletal stem cells because they do three important things: They become cells that make both cartilage and bone and support blood cell production.

This may be only one type of skeletal stem cells, Noriaki said, but it’s an important start.

“Understanding these special stem cells in the growth plate will help understand why some types of bone deformities and fragile bone diseases can happen in some patients,” he said.

The growth plate is composed of different layers, with the resting zone in the top layer. It’s long been thought that cells in the resting zone don’t divide, but Noriaki’s group discovered that some cells in the resting zone wake up and start to make rapidly dividing chondrocytes — cells that produce “beautiful” columns (that look like a stack of pancakes) and maintain bone growth.

Some of the cells in the resting zone go all the way from the top to the bottom layer of the growth plate, and some of them actually go through the growth plate and into the bone marrow cavity, creating osteoblasts (cells that make bone) and bone marrow stromal cells, which support blood cells.

Noriaki said he was surprised that the cells in the resting zone “weren’t just lazy and doing nothing, they’re very hardworking cells, they can occasionally wake up and keep making chondrocytes.”

It’s been hypothesized for many years that chondrocytes at the bottom of the growth plate die, but these findings show definite evidence that they survive and continue to make bone, he said.

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A comprehensive 'parts list' of the brain built from its components, the cells

Neuroscientists at the Allen Institute have moved one step closer to understanding the complete list of cell types in the brain. In the most comprehensive study of its kind to date, published today on the cover of the journal Nature, the researchers sorted cells from the cortex, the outermost shell and the cognitive center of the brain, into 133 different “cell types” based on the genes the cells switch on and off.

The classification, building off of 15 years of work at the Allen Institute, uncovered many rare brain cell types and laid the groundwork for revealing new functions of two of those rare neuron types. The study captured cell-by-cell information from parts of the mouse cortex that are involved in vision and movement.

Scientists are very far from understanding how the mammalian brain does what it does. They don’t even entirely know what it’s made of — the different types of brain cells. What neuroscientists are up against in their work is akin to trying to recreate a delicious, complex meal, not only without knowing the ingredients and recipe that went into making it, but without even having any way to describe many of those ingredients.

In the new study, the researchers came up with a way to describe those ingredients by analyzing the genes from nearly 24,000 of the mouse’s 100 million brain cells, creating a list of 133 cell types. Because the study captured the activity of tens of thousands of genes from so many cells and is nearly complete for the vision and motor regions in the study, the other regions of the cortex will likely follow similar rules of organization, the researchers said.

“This is by far the most comprehensive, most in-depth analysis of any regions of the cortex in any species. We can now say that we understand the distribution rules for its parts list,” said Hongkui Zeng, Ph.D., Executive Director of Structured Science at the Allen Institute for Brain Science, a division of the Allen Institute, and senior author on the study. “With all these data in hand, we can start to learn new principles of how the brain is organized — and ultimately, how it works.”

In an accompanying paper, also published today in Nature and led by researchers at the Janelia Research Campus of the Howard Hughes Medical Institute, the neuroscientists used the gene-based classification and additional information about neuron shape to uncover two new types of neurons involved in movement. The researchers then measured the activity of these different neurons in moving mice, and they found that one type is involved in planning movements, whereas the other type works to trigger movement itself.

“Gene expression is a very efficient way of getting at cell types, and that’s really what the Allen Institute effort is at the core,” said Janelia’s Karel Svoboda, Ph.D., who led the motor neuron study along with Michael Economo, Ph.D., and is also a co-author on the cell types study. “The motor cortex study is the first salvo in a different type of cell type classification, where gene expression information, structural information and measurements of neural activity are brought together to make statements about the function of specific cell types in the brain.”

Sifting through 24,000 cells to understand the brain

The mammalian cortex is considered the main brain region controlling cognitive function, and is far larger in humans than in most other mammals. Many researchers believe understanding the makeup of this complex but regularly ordered region of the brain will help us understand what makes mammal brains special — or what makes our brains uniquely human. The Allen Institute researchers are also working to define the “ingredients list” for the rest of the mouse cortex, although they expect that many of the rules of organization they’ve identified in this study will hold true across the entire region. And knowledge gained from the mouse cortex forms the foundation for understanding the human cortex through comparative studies.

Although there are many ways of understanding what makes one cell type different from another — its shape, how it sends electric signals, and how those signals translate into the brain’s many functions — only gene expression lends itself to studying tens of thousands of cells, one cell at a time, in a comprehensive way.

“It’s only through recent advances in technology that we can measure the activity of so many genes in a single cell,” said Bosiljka Tasic, Ph.D., Associate Director of Molecular Genetics at the Allen Institute for Brain Science and first author on the cell types study. “Ultimately, we are also working to study not only gene expression, but many of the cells’ other properties — including their function, which is the most elusive, the most difficult to define.”

The Allen Institute-led cell type study was built off a similar, smaller study completed in 2016, which sifted through about 1,600 cells from the mouse’s visual processing part of the brain. Scaling up the number of cells in their analysis by nearly 15 times and expanding to a second region of the brain cortex allowed the researchers to create a more comprehensive and refined cell type catalog.

“When we see not only cell types that people have identified before, but a number of new ones that are showing up in the data, it’s really exciting for us,” Zeng said. “It’s like we are able to put all the different pieces of the puzzle together and suddenly see the whole picture.”

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Breakthrough in treating paralysis

Three paraplegics who sustained cervical spinal cord injuries many years ago are now able to walk with the aid of crutches or a walker thanks to new rehabilitation protocols that combine targeted electrical stimulation of the lumbar spinal cord and weight-assisted therapy.

This latest study, called STIMO (STImulation Movement Overground), establishes a new therapeutic framework to improve recovery from spinal cord injury. All patients involved in the study recovered voluntary control of leg muscles that had been paralyzed for many years. Unlike the findings of two independent studies published recently in the United States on a similar concept, neurological function was shown to persist beyond training sessions even when the electrical stimulation was turned off. The STIMO study, led by the Ecole Polytechnique Fédérale de Lausanne (EPFL) and the Lausanne University Hospital (CHUV) in Switzerland, is published in the 1 November 2018 issues of Nature and Nature Neuroscience.

“Our findings are based on a deep understanding of the underlying mechanisms which we gained through years of research on animal models. We were thus able to mimic in real time how the brain naturally activates the spinal cord,” says EPFL neuroscientist Grégoire Courtine.

“All the patients could walk using body weight support within one week. I knew immediately that we were on the right path,” adds CHUV neurosurgeon Jocelyne Bloch, who surgically placed the implants in the patients.

“The exact timing and location of the electrical stimulation are crucial to a patient’s ability to produce an intended movement. It is also this spatiotemporal coincidence that triggers the growth of new nerve connections,” says Courtine.

This study achieves an unprecedented level of precision in electrically stimulating spinal cords. “The targeted stimulation must be as precise as a Swiss watch. In our method, we implant an array of electrodes over the spinal cord which allows us to target individual muscle groups in the legs,” explains Bloch. “Selected configurations of electrodes are activating specific regions of the spinal cord, mimicking the signals that the brain would deliver to produce walking.”

The challenge for the patients was to learn how to coordinate their brains’ intention to walk with the targeted electrical stimulation. But that did not take long. “All three study participants were able to walk with body-weight support after only one week of calibration, and voluntary muscle control improved tremendously within five months of training”, says Courtine. “The human nervous system responded even more profoundly to the treatment than we expected.”

Helping the brain help itself

The new rehabilitation protocols based on this targeted neurotechnology lead to improved neurological function by allowing the participants to actively train natural overground walking capabilities in the lab for extensive periods of time, as opposed to passive training like exoskeleton-assisted stepping.

During rehabilitation sessions, the three participants were able to walk hands-free over more than one kilometer with the help of targeted electrical stimulation and an intelligent bodyweight-support system. Moreover, they exhibited no leg-muscle fatigue, and so there was no deterioration in stepping quality. These longer, high-intensity training sessions proved crucial for triggering activity-dependent plasticity – the nervous system’s intrinsic ability to reorganize nerve fibers – which leads to improved motor function even when the electrical stimulation is turned off.

Previous studies using more empirical approaches, such as continuous electrical stimulation protocols, have shown that a select few paraplegics can indeed take steps with the help of walking aids and electrical stimulation, but only over short distances and as long as the stimulation is on. As soon as the stimulation is turned off, the patients immediately return to their previous state of paralysis and are no longer able to activate leg movements.

Next steps

The startup GTX medical, co-founded by Courtine and Bloch, will use these findings to develop tailored neurotechnology with the aim to turn this rehabilitation paradigm into a treatment available at hospitals and clinics everywhere. “We are building next-generation neurotechnology that will also be tested very early post-injury, when the potential for recovery is high and the neuromuscular system has not yet undergone the atrophy that follows chronic paralysis. Our goal is to develop a widely accessible treatment,” adds Courtine.

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Materials provided by Ecole Polytechnique Fédérale de Lausanne. Original written by H. Sanctuary and E. Barraud. Note: Content may be edited for style and length.

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Cooling 'brains on fire' to treat Parkinson's

A promising new therapy to stop Parkinson’s disease in its tracks has been developed at The University of Queensland.

UQ Faculty of Medicine researcher Associate Professor Trent Woodruff said the team found that a small molecule, MCC950, stopped the development of Parkinson’s in several animal models.

“We have used this discovery to develop improved drug candidates and hope to carry out human clinical trials in 2020,” Dr Woodruff said.

“Parkinson’s disease is the second-most common neurodegenerative disease worldwide, with 10 million sufferers, whose control of body movements is affected.

“The disease is characterised by the loss of brain cells that produce dopamine, which is a chemical that co-ordinates motor control, and is accompanied by chronic inflammation in the brain.

“We found a key immune system target, called the NLRP3 inflammasome, lights up in Parkinson’s patients, with signals found in the brain and even in the blood.

“MCC950, given orally once a day, blocked NLRP3 activation in the brain and prevented the loss of brain cells, resulting in markedly improved motor function.”

There are no medications on the market that prevent brain cell loss in Parkinson’s patients, with current therapies focusing on managing symptoms rather than halting the disease.

UQ Institute for Molecular Bioscience researcher Professor Matt Cooper said drug companies had traditionally tried to treat neurodegenerative disorders by blocking neurotoxic proteins that build up in the brain and cause disease.

“We have taken an alternative approach by focusing on immune cells in the brain called microglia that can clear these toxic proteins,” he said.

“With diseases of ageing such as Parkinson’s, our immune system can become over-activated, with microglia causing inflammation and damage to the brain.

“MCC950 effectively ‘cooled the brains on fire’, turning down microglial inflammatory activity, and allowing neurons to function normally.”

The study is published in Science Translational Medicine, and was made possible by generous support from The Michael J. Fox Foundation for Parkinson’s Research and Shake it Up Australia Foundation, which fund innovative research into therapies for Parkinson’s disease.

“We are extremely grateful to our funders who have supported multiple research projects on this target at UQ, and to their donors who support medical research for those living with Parkinson’s,” Dr Woodruff said.

The study was undertaken at the School of Biomedical Sciences and involved UQCCR Group Leader in Clinical Neuroscience Dr Richard Gordon, an Advance Queensland Research Fellow, and PhD student Eduardo Albornoz.

“The findings provide exciting new insight into how the spread of toxic proteins occurs in Parkinson’s disease and highlights the important role of the immune system in this process,” Dr Gordon said.

“With continued funding support, we are exploring new treatment strategies including repurposing drugs to target mechanisms by which the immune system and the inflammasome contribute to disease progression.”

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Amyloid assemblies once believed to be toxic found to play key role in muscle generation

Toxic protein assemblies, or “amyloids,” long considered to be key drivers in many neuromuscular diseases, also play a beneficial role in the development of healthy muscle tissue, University of Colorado Boulder researchers have found.

“Ours is the first study to show that amyloid-like structures not only exist in healthy skeletal muscle during regeneration, but are likely important for its formation,” said co-first author Thomas Vogler, an M.D./PhD candidate in the Department of Molecular, Cellular, and Developmental Biology (MCDB).

The surprising finding, published today in the journal Nature, sheds new light on the potential origins of a host of incurable disorders, ranging from amyotrophic lateral sclerosis (ALS) to inclusion body myopathy (which causes debilitating muscle degeneration) to certain forms of muscular dystrophy.

The researchers believe it could ultimately open new avenues for treating musculoskeletal diseases and also lend new understanding to related neurological disorders like Parkinson’s and Alzheimer’s disease, in which different amyloids play a role.

“Many of these degenerative diseases share a similar scenario in which they have these protein aggregates that accumulate in the cell and gum up the system,” said co-first author Joshua Wheeler, also an M.D./PhD candidate in the Department of Biochemistry. “As these aggregates are beneficial for normal regeneration, our data suggest that the cell is just damaged and trying to repair itself.”

For the study, Vogler and MCDB professor Brad Olwin, who study muscle generation, teamed up with Wheeler and Roy Parker, who study RNA, to investigate a protein called TDP-43.

TDP-43 has long been suspected to be a culprit in disease, having been found in the skeletal muscle of people with inclusion body myopathy and the neurons of people with ALS. But when the researchers closely examined muscle tissue growing in culture in the lab, they discovered clumps of TDP-43 were present not only in diseased tissue but also in healthy tissue.

“That was astounding,” said Olwin. “These amyloid-like aggregates, which we thought were toxic, seemed to be a normal part of muscle formation, appearing at a certain time and then disappearing again once the muscle was formed.”

Subsequent studies in muscle tissue growing in culture showed that when the gene that codes for TDP-43 was knocked out, muscles didn’t grow. When the researchers looked at human tissue biopsied from healthy people whose muscles were regenerating, they found aggregates, or “myo-granules,” of TDP-43. Further RNA-protein mapping analysis showed that the clusters — like shipping trucks traveling throughout the cell — appear to carry instructions for how to build contractile muscle fibers.

Wheeler and Vogler, both competitive runners and long-time friends, came up with the initial idea for the study while on a trail run. Wheeler says the data suggest that when healthy athletes push their muscles hard via things like marathons and ultramarathons, they are probably also forming amyloid-like clusters within their cells.

The key question remains: Why do most people quickly clear these proteins while others do not, with. the granules — like sugar cubes that won’t dissolve — clustering together and causing disease?

“If they normally form and go away, something is making them dissolve,” said Olwin. “Figuring out the mechanisms involved could potentially open a new avenue for treatments.”

The team is also interested in exploring whether a similar process may occur in the brain after injury, kick-starting disease. And subsequent studies will go even further to identify what the protein clusters do.

“This is a great example of how collaboration across disciplines can lead to really important work,” said Parker.

As participants in CU’s Medical Science Training Program, which enables students to concurrently pursue a medical degree at the Anschutz Medical Campus and a PhD at CU Boulder, Wheeler and Vogler hope that someday the work they do in the lab will help the patients they see in the clinic.

“The holy grail of all this is to be able to treat devastating and incurable diseases like ALS and to develop therapeutic strategies to improve skeletal muscle and fitness,” said Wheeler. “We are just opening the door on this.”