Parkinson gene: Nerve growth factor halts mitochondrial degeneration

Neurodegenerative diseases like Parkinson’s disease involve the death of thousands of neurons in the brain. Nerve growth factors produced by the body, such as GDNF, promote the survival of the neurons; however, clinical tests with GDNF have not yielded in any clear improvements. Scientists from the Max Planck Institute of Neurobiology in Martinsried and their colleagues have now succeeded in demonstrating that GDNF and its receptor Ret also promote the survival of mitochondria, the power plants of the cell. By activating the Ret receptor, the scientists were able to prevent in flies and human cell cultures the degeneration of mitochondria, which is caused by a gene defect related to Parkinson’s disease. This important new link could lead to the development of more refined GDNF therapies in the future.

In his “Essay on the Shaking Palsy” of 1817, James Parkinson provided the first description of a disease that today affects almost 280,000 people in Germany. The most conspicuous symptom of Parkinson’s disease is a slow tremor, which is usually accompanied by an increasing lack of mobility and movement in the entire body. These symptoms are visible manifestations of a dramatic change that takes place in the brain: the death of large numbers of neurons in the Substantia nigra of the midbrain.

Despite almost 200 years of research into Parkinson’s, its causes have not yet been fully explained. It appears to be certain that, in addition to environmental factors, genetic mutations also play a role in the emergence of the disease. A series of genes is now associated with Parkinson’s disease. One of these is PINK1, whose mutation causes mitochondrial dysfunction. Mitochondria are a cell’s power plants and without them, a cell cannot function properly or regenerate. Scientists from the Max Planck Institute of Neurobiology and their colleagues from Munich and Martinsried have now discovered a hitherto unknown link that counteracts mitochondrial dysfunction in the case of a PINK1 mutation.

The PINK1 gene emerged at a very early stage in evolutionary history and exists in a similar form for example in humans, mice and flies. In the fruit fly Drosophila, a mitochondrial defect triggered by a PINK1 mutation manifests in the fraying of the muscles. Less visible, the flies’ neurons also die. The scientists studied the molecular processes involved in these changes and discovered that the activation of the Ret receptor counteracts the muscle degeneration. “This is a really interesting finding which links the mitochondrial degeneration in Parkinson’s disease with nerve growth factors,” reports Rüdiger Klein, the head of the research study. Ret is not an unknown factor for the Martinsried-based neurobiologists: “We already succeeded in demonstrating a few years ago in mice that neurons without the Ret receptor die prematurely and in greater numbers with increasing age,” says Klein.

The Ret receptor is the cells’ docking site for the growth factor GDNF, which is produced by the body. Various studies carried out in previous years showed that the binding of GDNF to its Ret receptor can prevent the early death of neurons in the Substantia nigra. However, clinical studies on the influence of GDNF on the progression of Parkinson’s in patients did not lead to any clear improvement in their condition.

The new findings from basic research suggest that the mitochondrial metabolism is boosted or re-established through Ret/GNDF. “Based on this finding, existing therapies could be refined or tailored to specific patient groups,” hopes Pontus Klein, who conducted the study within the framework of his doctoral thesis. This hope does not appear to be completely unfounded: The scientists have already discovered a Ret/GDNF effect in human cells with a PINK1 defect similar to that observed in the fruit fly. It may therefore be possible to search for metabolic defects in the mitochondria of Parkinson’s patients in future. A specially tailored GDNF therapy could then provide a new therapeutic approach for patients who test positively.

Head first: reshaping how traumatic brain injury is treated

Traumatic brain injury affects 10 million people a year worldwide and is the leading cause of death and disability in children and young adults. A new study will identify how to match treatments to patients, to achieve the best possible outcome for recovery.

Switching brain development on, and off

The possibility of nerve cell regeneration is a step closer after neuroscientists identified the genetic signals that play a crucial role in normal development - driving stem cells to produce neurons that are correctly positioned and connected neurons within the brain.

Published in Cerebral Cortex, a study led by Dr Julian Heng of the Australian Regenerative Medicine Institute (ARMI) at Monash University, has identified a transcription factor, RP58, which is an important “off switch” for the process of nerve cell formation.

“Known as RP58, this gene switches off Rnd2 expression to control the proper positioning of neurons within the fetal brain - a crucial process,” Dr Heng said.

Absence of RP58 has been linked to a rare brain developmental disorder known as Terminal 1q deletion syndrome, where patients suffer reduced brain growth, experience epileptic seizures and are intellectually disabled.

Dr Heng’s work, on pre-clinical models, builds on previous research in which another transcription factor, Neurog2, operated as the “on-switch” for the crucial process of early brain development whereby stem cells become neurons.

Neurog2 switches on the expression of another gene, Rnd2, to control how new nerve cells of the developing brain find their appropriate location and go on to establish their proper connections. However, too much Rnd2 can impair the path-finding of new neurons, and so the researchers theorised that an “off-switch” controlled the process.

Dr Heng said that the discovery of RP58 was the proof needed to demonstrate that genes such as Rnd2 must be switched on, and then off in order for brain cells to assemble properly.

“Together with a collaborative study we published with our colleagues earlier in the year, this research demonstrates that loss of RP58 impairs the development of new nerve cells in the embryonic mouse brain, including their path-finding,” Dr Heng said.  

“Since the early steps of nerve cell production during brain development are comparable between mice and humans, we believe that RP58 carries out similar functions in the foetal human brain as well. This strengthens the notion that disruptions to this gene can cause brain developmental disease.”

Recently, a study led by researchers at Stanford University in the United States provided evidence showing that RP58 (also known as ZFP238) is crucial for the maturation of new human nerve cells.

Dr Heng believes his discoveries could be used in the context of regenerative medicine.

“Ultimately, the goal of our research is to understand the fundamental properties which control the production and maturation of new nerve cells in the brain. Understanding the function of switches like RP58 is crucial to this process,” Dr Heng said.

"In the future, we will use this knowledge to develop novel cell-based therapies to treat neurodegenerative disorders and brain injury.”

The iPod in the head: How the brain processes musical hallucinations

Sufferers persistently perceive music, as if they were hearing it with their ears, when no music is actually being played. Initially they often mistake the experience for actual music playing and while musical hallucinations can occasionally be a symptom of a neurological or psychiatric disorder, it is usually caused by hearing loss in people who are in normal physical and mental health.

Dr Sukhbinder Kumar from the Institute of Neuroscience at Newcastle University, lead author of the paper published in Cortex said: “We found that a network of brain areas, that are usually involved in processing of melodies and retrieval of memory of music, were particularly active during hallucinations of music in the absence of any sound or music being played externally.”

Nearly one in ten people suffer from tinnitus which is technically an auditory hallucination, in which tones or buzzing noises are heard following hearing loss. However in a small number of people with hearing loss these hallucinations take the form of music, but until now the brain mechanisms underlying this process were poorly understood.

This study by researchers at Newcastle University and University College London and funded by the Wellcome Trust has looked in depth at one sufferer of the condition and pinpointed the regions of the brain involved in producing the hallucinations. These findings could lead to a better understanding of the condition and possibly treatments in the future.

Musical hallucination

Sylvia, 69, a maths teacher who is also a musician with perfect pitch, started to go deaf about 20 years ago after a viral infection. Then about eleven years later she experienced a sudden acute hearing loss and severe tinnitus and her musical hallucinations developed after this. Due to her musical knowledge Sylvia was able to notate what she was hearing.

Initially the condition was irritating and affected Sylvia’s sleep, but she learnt to live with it. “I did everything I could to get rid of them but they persisted, always in a minor key and therefore a bit depressing,” she said.

“Eventually the number of notes increased until they seemed to be parts of tunes. One day I recognized something and, once I had done so, more and more phrases from classical music appeared in my brain.”

Among the pieces of music that Sylvia was hearing in her hallucinations was Gilbert and Sullivan’s HMS Pinafore, as well as music by Bach. Amazingly Sylvia found that by playing music herself, she was able to alter the music in her hallucinations.

“I can change the hallucination playing in my head to the music I am practising. This is particularly the case with the music of Bach - the hallucination will pause and then a whole page will start to play in my head, gradually curtailing itself until just a phrase remains and is repeated.  That might then repeat a thousand times a day. It is as if I have my own internal ipod.”

Sylvia’s experience is fairly typical, though the condition occurs just as often in non-musicians, and sometimes starts abruptly rather than slowly developing as in her case.

How we hear

As Sylvia’s hallucinations could be manipulated by playing an external piece of music that allowed the researchers to understand what was happening in her brain during hallucinations. They first identified pieces of music that suppressed her hallucinations and these pieces were then played to her while her brain activity was being monitored using magnetoencephalography MEG), which measures magnetic fields around the scalp as the brain processes information.

During normal perception of music what we actually ‘hear’ is a complex interplay of the sound entering the ear and our brain’s interpretations and predictions. Normally the strength and quality of the input from the ear is so high that it dominates what we actually perceive however the brain fills in the gaps when the ears do not provide enough input.

“With hearing loss, as in Sylvia’s case, the signal from the ear becomes weak and noisy, like a poorly-tuned radio. The brain’s predictive mechanisms therefore have to work very hard to make sense of what we are hearing. What we have found is that these processes sometimes end up running away with themselves to cause hallucinations,” said author Dr William Sedley also of Newcastle University.

Dr Kumar added: “This also explains why listening to an external piece of music suppresses hallucinations. When external music is playing the signal entering her brain is much stronger and more reliable, which constrains the aberrant communication going on in the brain areas during hallucinations.”

This new understanding of musical hallucinations may provide better treatment in the future as Newcastle University’s Professor Tim Griffiths, professor of Cognitive Neurology who lead the study explained: “It might be possible to disrupt the abnormal communication between the brain areas using brain stimulation, or to use pharmacological treatments to disrupt chemical transmitters that drive communication between them.

“Better hearing aids also appear to help suppress hallucinations, so we would advise people experiencing musical hallucinations to seek medical attention, if for nothing more than to ensure they have the best available hearing aids.”

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, says: “This case is extremely fascinating, but the condition is relatively rare. However, it is unusual cases such as this that can give us profound insights into how the brain works and, one hopes, lead to potential new treatments to improve the patient’s life.”

What makes us human? Unique brain area linked to higher cognitive powers

Oxford University researchers have identified an area of the human brain that appears unlike anything in the brains of some of our closest relatives.

The brain area pinpointed is known to be intimately involved in some of the most advanced planning and decision-making processes that we think of as being especially human.

'We tend to think that being able to plan into the future, be flexible in our approach and learn from others are things that are particularly impressive about humans. We've identified an area of the brain that appears to be uniquely human and is likely to have something to do with these cognitive powers,' says senior researcher Professor Matthew Rushworth of Oxford University's Department of Experimental Psychology.

MRI imaging of 25 adult volunteers was used to identify key components in the ventrolateral frontal cortex area of the human brain, and how these components were connected up with other brain areas. The results were then compared to equivalent MRI data from 25 macaque monkeys.

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Study Examines the Development of Children’s Prelife Reasoning

Most people, regardless of race, religion or culture, believe they are immortal. That is, people believe that part of themselves–some indelible core, soul or essence–will transcend the body’s death and live forever.  But what is this essence?  Why do we believe it survives?  And why is this belief so unshakable?

A new Boston University study led by postdoctoral fellow Natalie Emmons and published in the January 16, 2014 online edition of Child Development sheds light on these profound questions by examining children’s ideas about “prelife,” the time before conception. By interviewing 283 children from two distinct cultures in Ecuador, Emmons’s research suggests that our bias toward immortality is a part of human intuition that naturally emerges early in life. And the part of us that is eternal, we believe, is not our skills or ability to reason, but rather our hopes, desires and emotions. We are, in fact, what we feel.

Emmons’ study fits into a growing body of work examining the cognitive roots of religion. Although religion is a dominant force across cultures, science has made little headway in examining whether religious belief–such as the human tendency to believe in a creator–may actually be hard-wired into our brains.

“This work shows that it’s possible for science to study religious belief,” said Deborah Kelemen, an Associate Professor of Psychology at Boston University and co-author of the paper. “At the same time, it helps us understand some universal aspects of human cognition and the structure of the mind.”

Most studies on immortality or “eternalist” beliefs have focused on people’s views of the afterlife. Studies have found that both children and adults believe that bodily needs, such as hunger and thirst, end when people die, but mental capacities, such as thinking or feeling sad, continue in some form.  But these afterlife studies leave one critical question unanswered: where do these beliefs come from? Researchers have long suspected that people develop ideas about the afterlife through cultural exposure, like television or movies, or through religious instruction. But perhaps, thought Emmons, these ideas of immortality actually emerge from our intuition.  Just as children learn to talk without formal instruction, maybe they also intuit that part of their mind could exist apart from their body.

Emmons tackled this question by focusing on “prelife,” the period before conception, since few cultures have beliefs or views on the subject. “By focusing on prelife, we could see if culture causes these beliefs to appear, or if they appear spontaneously,” said Emmons.

“I think it’s a brilliant idea,” said Paul Bloom, a Professor of Psychology and Cognitive Science at Yale who was not involved with the study. “One persistent belief is that children learn these ideas through school or church. That’s what makes the prelife research so cool. It’s a very clever way to get at children’s beliefs on a topic where they aren’t given answers ahead of time.”

Emmons interviewed children from an indigenous Shuar village in the Amazon Basin of Ecuador. She chose the group because they have no cultural prelife beliefs, and she suspected that indigenous children, who have regular exposure to birth and death through hunting and farming, would have a more rational, biologically-based view of the time before they were conceived. For comparison, she also interviewed children from an urban area near Quito, Ecuador. Most of the urban children were Roman Catholic, a religion that teaches that life begins only at conception. If cultural influences were paramount, reasoned Emmons, both urban and indigenous children should reject the idea of life before birth.

Emmons showed the children drawings of a baby, a young woman, and the same woman while pregnant, then asked a series of questions about the child’s abilities, thoughts and emotions during each period: as babies, in the womb, and before conception.

The results were surprising.  Both groups gave remarkably similar answers, despite their radically different cultures. The children reasoned that their bodies didn’t exist before birth, and that they didn’t have the ability to think or remember. However, both groups also said that their emotions and desires existed before they were born. For example, while children generally reported that they didn’t have eyes and couldn’t see things before birth, they often reported being happy that they would soon meet their mother, or sad that they were apart from their family.

“They didn’t even realize they were contradicting themselves,” said Emmons. “Even kids who had biological knowledge about reproduction still seemed to think that they had existed in some sort of eternal form.  And that form really seemed to be about emotions and desires.”

Why would humans have evolved this seemingly universal belief in the eternal existence of our emotions? Emmons said that this human trait might be a by-product of our highly developed social reasoning. “We’re really good at figuring out what people are thinking, what their emotions are, what their desires are,” she said. We tend to see people as the sum of their mental states, and desires and emotions may be particularly helpful when predicting their behavior. Because this ability is so useful and so powerful, it flows over into other parts of our thinking. We sometimes see connections where potentially none exist, we hope there’s a master plan for the universe, we see purpose when there is none, and we imagine that a soul survives without a body.

These ideas, while nonscientific, are natural and deep-seated. “I study these things for a living but even find myself defaulting to them. I know that my mind is a product of my brain but I still like to think of myself as something independent of my body,” said Emmons.

“We have the ability to reflect and reason scientifically, and we have the ability to reason based on our gut and intuition,” she added. “And depending on the situation, one may be more useful than the other.”

Expanding our view of vision

Every time you open your eyes, visual information flows into your brain, which interprets what you’re seeing. Now, for the first time, MIT neuroscientists have noninvasively mapped this flow of information in the human brain with unique accuracy, using a novel brain-scanning technique.

This technique, which combines two existing technologies, allows researchers to identify precisely both the location and timing of human brain activity. Using this new approach, the MIT researchers scanned individuals’ brains as they looked at different images and were able to pinpoint, to the millisecond, when the brain recognizes and categorizes an object, and where these processes occur.

“This method gives you a visualization of ‘when’ and ‘where’ at the same time. It’s a window into processes happening at the millisecond and millimeter scale,” says Aude Oliva, a principal research scientist in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL).

Oliva is the senior author of a paper describing the findings in the Jan. 26 issue of Nature Neuroscience. Lead author of the paper is CSAIL postdoc Radoslaw Cichy. Dimitrios Pantazis, a research scientist at MIT’s McGovern Institute for Brain Research, is also an author of the paper.

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