Removing protein ‘garbage’ in nerve cells may help control 2 neurodegenerative diseases

Neuroscientists at Georgetown University Medical Center say they have new evidence that challenges scientific dogma involving two fatal neurodegenerative diseases — amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) — and, in the process, have uncovered a possible therapeutic target as a novel strategy to treat both disorders.

The study, posted online in the Journal of Biological Chemistry, found that the issue in both diseases is the inability of the cell’s protein garbage disposal system to “pull out” and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron.

"This finding suggests that if we’re able to ‘rev up’ that clearance machinery and help the cell get rid of the bad actors, it could possibly reduce or slow the development of ALS and FTD," says the study’s lead investigator, neuroscientist Charbel E-H Moussa, MB, PhD. "The potential of such an advance is very exciting." He cautions, though, that determining if this strategy is possible in humans could take many years and will involve teams of researchers.

The way to rev up protein disposal is to add parkin — the cell’s natural disposal units — to brain cells. In this study, Moussa and his colleagues demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43.”

Moussa says that his study further demonstrates that clumps known as “inclusions” of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued.

What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig’s disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia.

"In both diseases, TDP-43 is over-expressed or mutated, and the scientific debate has been whether loss of TDP-43 in the nucleus or gain of TDP-43 in the cytoplasm is the problem," Moussa says.

"Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed — without contributing to disease — and that TDP-43 in the nucleus is causing the damage," he says. "Because so much protein is being produced, the cell can’t keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem."

Moussa has long studied parkin, a molecule best known, when mutated and inactive, for its role in a familial form of Parkinson’s disease. He has studied it in Alzheimer’s disease and other forms of dementia. His hypothesis, which he has demonstrated in several recently published studies, is that parkin could help remove the toxic fragments of amyloid beta protein that builds up in the brains of Alzheimer’s disease patients.

What’s more, he developed a method to clear this amyloid beta when it begins to build up in neurons — a gene therapy strategy he has shown works in rodents. Work continues on this potential therapy.

In this study, Moussa found that parkin “tags” TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. “This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity,” he says.

"This discovery challenges the dogma that accumulation of TDP-43 in the cytoplasm is," Moussa says. "We think parkin is tagging proteins in the nucleus for destruction, but there just isn’t enough parkin around — compared with over-production of TDP-43 — to do the job."

Moussa says his next research steps will be to inject a drug that activates parkin to see whether that can prolong the lifespan and reduce motor defects in mice with ALS.

(Image: iStock)

Brain imaging insight into cannabis as a pain killer

The pain relief offered by cannabis varies greatly between individuals, a brain imaging study carried out at the University of Oxford suggests.

The researchers found that an oral tablet of THC, the psychoactive ingredient in cannabis, tended to make the experience of pain more bearable, rather than actually reduce the intensity of the pain.

MRI brain imaging showed reduced activity in key areas of the brain that substantiated the pain relief the study participants experienced. 

'We have revealed new information about the neural basis of cannabis-induced pain relief,' says lead researcher Dr Michael Lee of Oxford University's Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB). 

'Cannabis does not seem to act like a conventional pain medicine. Some people respond really well, others not at all, or even poorly,' he says. 'Brain imaging shows little reduction in the brain regions that code for the sensation of pain, which is what we tend to see with drugs like opiates. Instead cannabis appears to mainly affect the emotional reaction to pain in a highly variable way.'

Long-term pain, often without clear cause, is a complex healthcare problem. Different approaches are often needed to help patient manage pain, and can include medications, physiotherapy and other forms of physical therapy, and psychological support. 

For a few patients, cannabis or cannabis-based medications remain effective when other drugs have failed to control pain, while others report very little effect of the drug on their pain but experience side-effects.

'We know little about cannabis and what aspects of pain it affects, or which people might see benefits over the side-effects or potential harms in the long term. We carried out this study to try and get at what is happening when someone experiences pain relief using cannabis,' says Dr Lee.

He adds: ‘Our small-scale study, in a controlled setting, involved 12 healthy men and only one of many compounds that can be derived from cannabis. That’s quite different from doing a study with patients.

'My view is the findings are of interest scientifically but it remains to see how they impact the debate about use of cannabis-based medicines. Understanding cannabis' effects on clinical outcomes, or the quality of life of those suffering chronic pain, would need research in patients over long time periods.'

(The paper ‘Amygdala activity contributes to the dissociative effect of cannabis on pain perception' by Michael C. Lee, Markus Ploner, Katja Wiech, Ulrike Bingel, Vishvarani Wanigasekera, Jonathan Brooks, David K. Menon, Irene Tracey (DOI: 10.1016/j.pain.2012.09.017) will appear in PAIN®, Volume 154, Issue 1 (January 2013) published by Elsevier)

Discovery could eventually help diagnose and treat chronic pain

More than 100 million Americans suffer from chronic pain. But treating and studying chronic pain is complex and presents many challenges. Scientists have long searched for a method to objectively measure pain and a new study from Brigham and Women’s Hospital advances that effort. The study appears in the January 2013 print edition of the journal Pain.

"While we need to be cautious in the interpretation of our results, this has the potential to be an exciting discovery for anyone who suffers from chronic pain," said Marco Loggia, PhD, the lead author of the study and a researcher in the Pain Management Center at BWH and the Department of Radiology at Massachusetts General Hospital. "We showed that specific brain patterns appear to track the severity of pain reported by patients, and can predict who is more likely to experience a worsening of chronic back pain while performing maneuvers designed to induce pain. If further research shows this metric is reliable, this is a step toward developing an objective scale for measuring pain in humans."

Specifically, researchers studied 16 adults with chronic back pain and 16 adults without pain and used a brain imaging technique called arterial spin labeling to examine patterns of brain connectivity (that is, to examine how different brain regions interact, or “talk to each other”). They found that when a patient moved in a way that increased their back pain, a network of brain regions called Default Mode Network exhibited changes in its connections. Regions within the network (such as the medial prefrontal cortex) became less connected with the rest of the network, whereas regions outside network (such as the insula) became connected with this network. Some of these observations have been noted in previous studies of fibromyalgia patients, which suggests these changes in brain connectivity might reflect a general feature of chronic pain, possibly common to different patient populations.

"This is the first study using arterial spin labeling to show common networking properties of the brain are affected by chronic pain," said study author Ajay Wasan, MD, MSc, Director of the Section of Clinical Pain Research at BWH. "This novel research supports the use of arterial spin labeling as a tool to evaluate how the brain encodes and is affected by clinical pain, and the use of resting default mode network connectivity as a potential neuroimaging biomarker for chronic pain perception."

Evolution: It’s all in how you splice it

MIT biologists find that alternative splicing of RNA rewires signaling in different tissues and may often contribute to species differences.

When genes were first discovered, the canonical view was that each gene encodes a unique protein. However, biologists later found that segments of genes can be combined in different ways, giving rise to many different proteins.

This phenomenon, known as alternative RNA splicing, often alters the outputs of signaling networks in different tissues and may contribute disproportionately to differences between species, according to a new study from MIT biologists.

After analyzing vast amounts of genetic data, the researchers found that the same genes are expressed in the same tissue types, such as liver or heart, across mammalian species. However, alternative splicing patterns — which determine the segments of those genes included or excluded — vary from species to species.

“The core things that make a heart a heart are mostly determined by a heart-specific gene expression signature. But the core things that make a mouse a mouse may disproportionately derive from splicing patterns that differ from those of rats or other mammals” says Chris Burge, an MIT professor of biology and biological engineering, and senior author of a paper on the findings in the Dec. 20 online edition of Science.

Lead author of the paper is MIT biology graduate student Jason Merkin. Other authors are Caitlin Russell, a former technician in Burge’s lab, and Ping Chen, a visiting grad student at MIT.

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Researchers uncover major source of evolutionary differences among species

University of Toronto Faculty of Medicine researchers have uncovered a genetic basis for fundamental differences between humans and other vertebrates that could also help explain why humans are susceptible to diseases not found in other species.

Scientists have wondered why vertebrate species, which look and behave very differently from one another, nevertheless share very similar repertoires of genes. For example, despite obvious physical differences, humans and chimpanzees share a nearly identical set of genes.

The team sequenced and compared the composition of hundreds of thousands of genetic messages in equivalent organs, such as brain, heart and liver, from 10 different vertebrate species, ranging from human to frog. They found that alternative splicing — a process by which a single gene can give rise to multiple proteins — has dramatically changed the structure and complexity of genetic messages during vertebrate evolution.

The results suggest that differences in the ways genetic messages are spliced have played a major role in the evolution of fundamental characteristics of species. However, the same process that makes species look different from one another could also account for differences in their disease susceptibility.

"The same genetic mechanisms responsible for a species’ identity could help scientists understand why humans are prone to certain diseases such as Alzheimer’s and particular types of cancer that are not found in other species," says Nuno Barbosa-Morais, the study’s lead author and a computational biologist in U of T Faculty of Medicine’s Donnelly Centre for Cellular and Biomolecular Research. "Our research may lead to the design of improved approaches to study and treat human diseases."

One of the team’s major findings is that the alternative splicing process is more complex in humans and other primates compared to species such as mouse, chicken and frog.

"Our observations provide new insight into the genetic basis of complexity of organs such as the human brain," says Benjamin Blencowe, Professor in U of T’s Banting and Best Department of Research and the Department of Molecular Genetics, and the study’s senior author.

"The fact that alternative splicing is very different even between closely related vertebrate species could ultimately help explain how we are unique."

Dragonflies have human-like ‘selective attention’

In a discovery that may prove important for cognitive science, our understanding of nature and applications for robot vision, researchers at the University of Adelaide have found evidence that the dragonfly is capable of higher-level thought processes when hunting its prey.

The discovery, published online in the journal Current Biology, is the first evidence that an invertebrate animal has brain cells for selective attention, which has so far only been demonstrated in primates.

Dr Steven Wiederman and Associate Professor David O’Carroll from the University of Adelaide’s Centre for Neuroscience Research have been studying insect vision for many years.

Using a tiny glass probe with a tip that is only 60 nanometres wide - 1500 times smaller than the width of a human hair - the researchers have discovered neuron activity in the dragonfly’s brain that enables this selective attention.

They found that when presented with more than one visual target, the dragonfly brain cell ‘locks on’ to one target and behaves as if the other targets don’t exist.

"Selective attention is fundamental to humans’ ability to select and respond to one sensory stimulus in the presence of distractions," Dr Wiederman says.

Associate Professor O’Carroll says this brain activity makes the dragonfly a more efficient and effective predator.

"Recent studies reveal similar mechanisms at work in the primate brain, but you might expect it there. We weren’t expecting to find something so sophisticated in lowly insects from a group that’s been around for 325 million years, Associate Professor O’Carroll says.

"We believe our work will appeal to neuroscientists and engineers alike. For example, it could be used as a model system for robotic vision. Because the insect brain is simple and accessible, future work may allow us to fully understand the underlying network of neurons and copy it into intelligent robots," he says.

Will we ever… have cyborg brains?

For the first time in over 15 years, Cathy Hutchinson brought a coffee to her lips and smiled. Cathy had suffered from the paralysing effects of a stroke, but when neurosurgeons implanted tiny recording devices in her brain, she could use her thought patterns to guide a robot arm that delivered her hot drink. This week, it was reported that Jan Scheuermann, who is paralysed from the neck down, could grasp and move a variety of objects by controlling a robotic arm with her mind.

In both cases the implants convert brain signals into digital commands that a robotic device can follow. It’s a remarkable achievement, one that could transform the lives of people debilitated through illness.

Yet it’s still a far cry from the visions of man fused with machine, or cyborgs, that grace computer games or sci-fi. The dream is to create the type of brain augmentations we see in fiction that provide cyborgs with advantages or superhuman powers. But the ones being made in the lab only aim to restore lost functionality – whether it’s brain implants that restore limb control, or cochlear implants for hearing.

Creating implants that improve cognitive capabilities, such as an enhanced vision “gadget” that can be taken from a shelf and plugged into our brain, or implants that can restore or enhance brain function is understandably a much tougher task. But some research groups are being to make some inroads.

For instance, neuroscientists Matti Mintz from Tel Aviv University and Paul Verschure from Universitat Pompeu Fabra in Barcelona, Spain, are trying to develop an implantable chip that can restore lost movement through the ability to learn new motor functions, rather than regaining limb control. Verschure’s team has developed a mathematical model that mimics the flow of signals in the cerebellum, the region of the brain that plays an important role in movement control. The researchers programmed this model onto a circuit and connected it with electrodes to a rat’s brain. If they tried to teach the rat a conditioned motor reflex – to blink its eye when it sensed an air puff – while its cerebellum was “switched off” by being anaesthetised, it couldn’t respond. But when the team switched the chip on, this recorded the signal from the air puff, processed it, and sent electrical impulses to the rat’s motor neurons. The rat blinked, and the effect lasted even after it woke up.

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Study reveals how the brain categorizes thousands of objects and actions

Humans perceive numerous categories of objects and actions, but where are these categories represented spatially in the brain?

Researchers reporting in the December 20 issue of the Cell Press journal Neuron present their study that undertook the remarkable task of determining how the brain maps over a thousand object and action categories when subjects watched natural movie clips. The results demonstrate that the brain efficiently represents the diversity of categories in a compact space. Instead of having a distinct brain area devoted to each category, as previous work had identified, for some but not all types of stimuli, the researchers uncovered that brain activity is organized by the relationship between categories.

"Humans can recognize thousands of categories. Given the limited size of the human brain, it seems unreasonable to expect that every category is represented in a distinct brain area," says first author Alex Huth, a graduate student working in Dr. Jack Gallant’s laboratory at the University of California, Berkeley. The authors proposed that perhaps a more efficient way for the brain to represent object and action categories would be to organize them into a continuous space that reflects the similarity between categories.

To test this hypothesis, they used blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) to measure human brain activity evoked by natural movies in five people. They then mapped out how 1,705 distinct object and action categories are represented across the surface of the cortex of the brain. Their results show that categories are organized as smooth gradients that cover much of the surface of the visual as well as nonvisual cortex, such that similar categories are located next to each other, and notably, this organization was shared across the individuals imaged.

"Discovering the feature space that the brain uses to represent information helps us to recover functional maps across the cortical surface. The brain probably uses similar mechanisms to map other kinds of information across the cortical surface, so our approach should be widely applicable to other areas of cognitive neuroscience," says Dr. Gallant.