Chemical reaction keeps Stroke-damaged brain from repairing itself

Stuart A. Lipton, M.D., Ph.D., is director of the Del E. Webb Neuroscience, Aging, and Stem Cell Research Center at Sanford-Burnham Medical Research Institute and a clinical neurologist. 

Credit: Sanford-Burnham Medical Research Institute.

Nitric oxide, a gaseous molecule produced in the brain, can damage neurons.

When the brain produces too much nitric oxide, it contributes to the severity and progression of stroke and neurodegenerative diseases such as Alzheimer's.

Researchers at Sanford-Burnham Medical Research Institute recently discovered that nitric oxide not only damages neurons, it also shuts down the brain's repair mechanisms.

Their study was published by the Proceedings of the National Academy of Sciences (PNAS) the week of February 4.

"In this study, we've uncovered new clues as to how natural chemical reactions in the brain can contribute to brain damage—loss of memory and cognitive function—in a number of diseases," said Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham's Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.

Lipton led the study, along with Sanford-Burnham's Tomohiro Nakamura, Ph.D., who added that these new molecular clues are important because "we might be able to develop a new strategy for treating stroke and other disorders if we can find a way to reverse nitric oxide's effect on a particular enzyme in nerve cells."

Nitric oxide inhibits the neuroprotective ERK1/2 signaling pathway Learning and memory are in part controlled by NMDA-type glutamate receptors in the brain.

These receptors are linked to pores in the nerve cell membrane that regulate the flow of calcium and sodium in and out of the nerve cells. When these NMDA receptors get over-activated, they trigger the production of nitric oxide.

In turn, nitric oxide attaches to other proteins via a reaction called S-nitrosylation, which was first discovered by Lipton and colleagues. When those S-nitrosylated proteins are involved in cell survival and lifespan, nitric oxide can cause brain cells to die prematurely—a hallmark of neurodegenerative disease.

In their latest study, Lipton, Nakamura and colleagues used cultured neurons as well as a living mouse model of stroke to explore nitric oxide's relationship with proteins that help repair neuronal damage.

They found that nitric oxide reacts with the enzyme SHP-2 to inhibit a protective cascade of molecular events known as the ERK1/2 signaling pathway. Thus, nitric oxide not only damages neurons, it also blocks the brain's ability to self-repair.

Motor Neurone Disease: New Insight about how it works

When we imagine how research results can change society or help us make new bounds in medical science we think of proving a hypothesis or cracking a code, but sometimes research that refutes a theory can be just as beneficial, as scientists can eliminate a hypothesis from the mix and save years of wasted-time investigating dead ends and a team of German researchers has just done exactly that.

Writing in the journal Proceedings of the National Academy of Sciences (PNAS), the team refute a widely accepted hypothesis about a causative step in neuro-degenerative conditions.

These results deal specifically with animal models of human amyotrophic lateral sclerosis (ALS), more commonly known as Motor Neurone Disease, but the findings also have implications for other neuro-degenerative diseases such as Alzheimer's or Huntington's disease.

One of the ways neuro-degenerative diseases manifest themselves is in the loss of axons - essentially, the transmission lines for electrical signals in individual nerve cells - and synapses, the key sites for communication between them.

In the past, such damage has been attributed to deficits in the bi-directional transport of organelles, such as the intracellular power plants called mitochondria, along the axons of nerve cells.

The team, from the Technische Universitaet Muenchen (TUM) and Ludwig-Maximilians-Universitaet Muenchen (LMU), put these previously-held assumptions to the test in one of the most thorough tests carried out to date.

They used novel imaging techniques, with high resolution in both space and time, to observe changes in both axon morphology and organelle transport in several different animal models of ALS.

Their results show that transport deficits and axon degeneration can develop independently of each other, throwing into question the theory that one is a direct cause of the other.

They observed axonal organelle transport in living tissue in real time, and in a way that enabled them to track the movement of individual mitochondria, using a novel imaging approach that involves transgenic labelling.

They were also able to observe transport of another kind of organelle, endosome-derived vesicles. Several different animal models of ALS were investigated, all of which are based on human mutations associated with the disease.

One of the study authors, Professor Thomas Misgeld from the Institute of Neuroscience at the Technische Universitaet Muenchen, comments on their findings: 'We do think these insights have implications for other studies of ALS, or even studies of other neuro-degenerative diseases.

What our experiments really say is that it is not easy to develop faithful models of neuro-degenerative diseases.

So it might be worth spending more effort to get better animal models, as this is the only way forward for mechanistic studies, while always checking them against human pathology or human-derived cellular models.

In the meantime, it is probably prudent to work with several of the available models in parallel. Moreover, in more general biological terms, our results also speak to the relationship between axonal transport disruptions and degeneration - which might not be as tight as we assumed. Here we have a lot more to understand.'

The iPSoALS project brings together researchers from France, Germany, Israel and Sweden with the aim of better understanding ALS disease mechanisms.

For more information, please visit: Technische Universitaet Muenchen (TUM)

How Has Stephen Hawking Lived to 70 with Motor Neuron Disease

Stephen Hawking turns 70 on Sunday, beating the odds of a daunting diagnosis by nearly half a century.

The famous theoretical physicist has helped to bring his ideas about black holes and quantum gravity to a broad public audience.

For much of his time in the public eye, though, he has been confined to a wheelchair by a form of the motor-neuron disease amyotrophic lateral sclerosis (ALS).

Since 1985 he has had to speak through his trademark computer system—which he operates with his cheek—and have around-the-clock care.

But his disease seems hardly to have slowed him down. Hawking spent 30 years as a full professor of mathematics at the University of Cambridge. And he is currently the director of research at the school's Center for Theoretical Cosmology.

Like his mind, Hawking's illness seems to be almost unique. Most patients with ALS—also known as Lou Gehrig's disease, from a famous US baseball player who succumbed to the disease, are diagnosed after the age of 50 and die within five years of their diagnosis.

Hawking's condition was first diagnosed when he was 21, and he was not expected to see his 25th birthday.

Why has Hawking lived so long with this malady when so many other people die so soon after diagnosis?

We spoke with Leo McCluskey, an associate professor of neurology and medical director of the ALS Center at the University of Pennsylvania, to find out more about the disease and why it has spared Hawking and his amazing brain.

Read more of this article and interview: How Has Stephen Hawking Lived to 70 with ALS?

Sam Blackburn: The voice behind Stephen Hawking at 70

Sam Blackburn has been Hawking’s technician since 2006. And for these 5 years, he’s the one responsible for the technology that has allowed Hawking to communicate through a computer and a voice synthesizer by twitching his cheek.

When he was diagnosed with motor neurone disease (or ALS) at 21, physicist Stephen Hawking was only expected to live a few years. He turns 70 this week.

Since about 1986, he’s had to use a menu controlled by a computer system to speak. A computer highlights cells in a big grid of letters or words, and when the correct one is highlighted, he presses a switch.

But when he became unable to move his hands sufficiently, he moved to an infrared system mounted on his glasses, which detects movement in his cheek muscle. His facial muscles are the only ones he can control reasonably well.

When Blackburn first started, the system was breaking all the time. “I’d get calls at 1 o’clock in the morning saying ‘Stephen can’t speak, what do we do?’” he says. “So I needed to modernize the system.”

He did so incrementally, so the learning wouldn’t be too steep. “Stephen wouldn’t be able to ask for help because the very thing he wouldn’t be able to use would be the speech system,” he says. “Understandably that has made him very reluctant to upgrade.”

The only copy of Hawking’s hardware voice synthesizer is contained in a little gray box in Blackburn’s office. The card inside dates back to the 80s, and this particular one contains Hawking’s voice. There’s a processor on it that has a unique program that turns text into speech that sounds like Hawking’s, and they have only two of these cards.

The company that made them went bankrupt and nobody knows how it works any more. Blackburn is trying to reverse engineer it since they can’t just update the system with a new synthesizer.

“The voice is one of the unique things that defines Stephen in my opinion,” he explains. “He could easily change to a voice that was clearer, perhaps more soothing to listen to – less robotic sounding – but it wouldn’t be Stephen’s voice any more.”

However, Hawking’s progressive nerve decay means that his ability to control his cheek muscle is fading.

His rate of speech is down to about one word per minute. And while Blackburn’s been making slight advances in the current technology, they’re gonna have to move on to something new – like eye-tracking or brain scanning systems.

The challenge for Blackburn’s successor: to keep that well-known voice in working order.

Gardening in the Brain: Cells Called Microglia Prune the Connections Between Neurons

Microglia (green) in a mouse brain. The nuclei of all cells in the brain are labelled blue. (Credit: EMBL/R. Paolicelli)

Gardeners know that some trees require regular pruning: some of their branches have to be cut so that others can grow stronger.

The same is true of the developing brain: cells called microglia prune the connections between neurons, shaping how the brain is wired, scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, discovered. Published online in Science, the findings could one day help understand neurodevelopmental disorders like autism.

"We're very excited, because our data shows microglia are critical to get the connectivity right in the brain," says Cornelius Gross, who led the work: "they 'eat up' synapses to make space for the most effective contacts between neurons to grow strong."

Microglia are related to the white blood cells that engulf pathogens and cellular debris, and scientists knew already that microglia perform that same clean-up task when the brain is injured, 'swallowing up' dead and dying neurons.

Looking at the developing mouse brain under the microscope, Gross and colleagues found proteins from synapses -- the connections between neurons -- inside microglia, indicating that microglia are able to engulf synapses too.

To probe further, the scientists introduced a mutation that reduced the number of microglia in the developing mouse brain.

"What we saw was similar to what others have seen in at least some cases of autism in humans: many more connections between neurons," Gross says. "So we should be aware that changes in how microglia work might be a major factor in neurodevelopmental disorders that have altered brain wiring."

The microglia-limiting mutation the EMBL scientists used has only temporary effects, so eventually the number of microglia increases and the mouse brain establishes the right connections.

However, this happens later in development than it normally would, and Gross and colleagues would now like to find out if that delay has long-term consequences.

Does it affect the behaviour of the mice behaviour, for example? At the same time, Gross and colleagues plan to investigate what microglia do in the healthy adult brain, where their role is essentially unknown.

Gene switch rejuvenates failing mouse brains

Gene switch rejuvenates failing mouse brains

Step aside, Sudoku. A genetic switch that causes memory impairment in ageing mice when it goes into "off" mode has been flicked on, restoring failing brains to a more youthful state.

If a similar switch can be found in people, it might provide a new way to keep ageing human brains young.
Cognitive decline, particularly memory impairment, is a normal part of ageing in humans and animals. Yet why this happens, and how we can prevent it, is largely unknown, says David Sweatt at the University of Alabama, Birmingham, who was not involved in the new work.

André Fischer of the European Neuroscience Institute in Göttingen, Germany, and colleagues forced 3-month-old mice to find their way around a new environment and assessed them on their ability to associate an electric shock with a particular environment.

New neurons
The result was increased activity of a cluster of over 1500 genes which are known make proteins that are needed for the creation of new neurons – a process that is necessary for learning in humans and mice.

This boost in gene expression did not occur in 16-month-old mice given the same tasks: the activity of their genes changed only slightly. The mice also did worse than the young ones at spatial learning and memory tasks.

To uncover what prevents elderly mice getting this genetic boost, Fischer analysed the DNA found in neurons in the hippocampus of both old and young mice.

They found that when young mice are learning, a molecular fragment known as an acetyl group binds to a particular point on the histone protein that DNA wraps itself around – with the result that the cluster of learning and memory genes on the surrounding DNA ends up close to the acetyl group.

DNA 'on' switch
This acetyl "cap" was missing in the older mice that had been set the same tasks. From this, the team concludes that the cap acts as an "on" switch for the cluster of learning and memory genes: removing the cap switches off the genes.

Next, by injecting an enzyme known to encourage caps to bind to any kind of histone molecule, Fischer's team artificially flipped the switch to the on position in old mice. The acetyl group returned to the histone molecule and the mice's learning and memory performance became similar to that of 3-month-old mice.

The Gruesome Power of Raptor Talons

The most thorough study to date of raptor talons reveals their feet to be extraordinarily specialized hunting tools, perfectly suited to their gruesomely amazing killing strategies.

”Despite the ubiquity of raptors in terrestrial ecosystems, many aspects of their predatory behavior remain poorly understood,” wrote ornithologists in a paper published Wednesday in PLoS ONE.

“Surprisingly little is known about the morphology of raptor talons and how they are employed during feeding behavior.”

To get a better understanding, the researchers took detailed measurements of the talons from 24 bird of prey species, and linked them to literature on raptor hunting and 170 videos of attacks.

They describe how accipitrids, which include hawks and eagles, have two giant talons on their first and second toes. These give them a secure grip on struggling game that they like to eat alive, “so long as it does not protest too vigorously. In this prolonged and bloody scenario, prey eventually succumb to massive blood loss or organ failure, incurred during dismemberment.”

Meanwhile, the talons of owls, which don’t usually land a killing blow as they strike, are relatively short but strong, and one toe actually swivels backwards. That lets owls crush wounded quarry between two pairs of opposable talons. The animal is then swallowed whole.

Falcons are so skilled at disabling prey with a mid-air, high-speed strike that their talons are smaller than those of other raptors. They just don’t need them as much. Once they’ve landed, falcons “will quickly pluck the neck area and attempt to kill prey swiftly by breaking the neck with a bite attack.”

Osprey have large, curved talons, almost like fishhooks — which is appropriate because they specialize in catching fish, swooping down and hitting them just below the water’s surface.

In addition to expanding understanding of these much-loved birds, the findings could help researchers understand the birds’ dinosaur ancestors. The researchers are now studying how dinosaur claws reflected their hunting and feeding habits.

Image: (A) goshawk (B) red-tailed hawk (C) peregrine falcon (D) great grey owl (E) osprey./PLoS ONE

Herding the followers

HITLER and Mussolini both had the ability to bend millions of people to their fascist will. Now evidence from psychology and neurology is emerging to explain how tactics like organised marching and propaganda can work to exert mass mind control.

Scott Wiltermuth of Stanford University in California and colleagues have found that activities performed in unison, such as marching or dancing, increase loyalty to the group. "It makes us feel as though we're part of a larger entity, so we see the group's welfare as being as important as our own," he says.

Wiltermuth's team separated 96 people into four groups who performed these tasks together: listening to a song while silently mouthing the words, singing along, singing and dancing, or listening to different versions of the song so that they sang and danced out of sync. In a later game, when asked to decide whether to stick with the group or strive for personal gain, those in the non-synchronised group behaved less loyally than the rest (Psychological Science, vol 20, p 1).

Psychologist Jonathan Haidt at the University of Virginia in Charlottesville thinks this research helps explain why fascist leaders, amongst others, use organised marching and chanting to whip crowds into a frenzy of devotion to their cause, though these tactics can be used just as well for peace, he stresses. Community dances and group singing can ease local tension, for example - a theory he plans to test experimentally (Journal of Legal Studies, DOI: 10.1086/529447).

Meanwhile, the powerful unifying effects of propaganda images are being explored by Charles Seger at Indiana University at Bloomington. His team primed students with pictures of their university - college sweatshirts or the buildings themselves - then asked how highly they scored on different emotions, such as pride or happiness. The primed students gave a strikingly similar emotional profile, in contrast with non-primed students (Journal of Experimental Social Psychology, DOI: 10.1016/j.jesp.2008.12.004).

Interest in the idea of a herd mentality has been renewed by work into mirror neurons - cells that fire when we perform an action or watch someone perform a similar action. It suggests that our brains are geared to mimic our peers. "We are set up for 'auto-copy'," says Haidt. Interest in the idea of a herd mentality has been renewed by research into mirror neurons

Neurological evidence seems to back this idea. Vasily Klucharev, at the Donders Centre for Cognitive Neuroimaging in Nijmegen, the Netherlands, found that the brain releases more of the reward chemical dopamine when we fall in line with the group consensus (Neuron, vol 61, p 140). His team asked 24 women to rate more than 200 women for attractiveness. If a participant discovered their ratings did not tally with that of the others, they tended to readjust their scores. When a woman realised her differing opinion, fMRI scans revealed that her brain generated what the team dubbed an "error signal". This has a conditioning effect, says Klucharev: it's how we learn to follow the crowd