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)

Reversing age-associated effects in MS patients

New research highlights the possibility of reversing ageing in the central nervous system for multiple sclerosis (MS) patients.

The study is published today, 06 January, in the journal Cell Stem Cell.

As we get older, our bodies' ability to regenerate decreases. This is not only true for our skin (which is evident in the wrinkles that develop as we age) but also true for other tissues in the body, including the regenerative processes in the brain.

For diseases which often span several decades and are affected by regenerative processes, such as multiple sclerosis, this can have massive implications.

In multiple sclerosis, the insulating layers that protect nerve fibres in the brain, known as myelin sheaths, become damaged.

The loss of myelin in the brain prevents nerve fibres from sending signals properly and will eventually lead to the loss of the nerve fibre itself.

However, early in the disease, a regenerative process, or remyelination, occurs and the myelin sheaths are restored. Unfortunately, as people with MS age, remyelination decreases significantly, resulting in more nerve fibres being permanently lost.

However, a new study in mice shows that the age-associated decline in the regeneration of the nerve's myelin sheath, or remyelination, is reversible.

The proof of principle study demonstrates that when old mice are exposed to the inflammatory cells (called monocytes) from young mice, the ageing remyelination process can be reversed.

Professor Robin Franklin, Director of the MS Society's Cambridge Centre for Myelin Repair at the University of Cambridge, said: "What we have shown in our study, carried out in collaboration with Dr Amy Wagers and colleagues at Harvard University, is that the age-associated decline in remyelination is reversible.

We found that remyelination in old adult mice can be made to work as efficiently as it does in young adult mice.

"For individuals with MS, this means that in theory regenerative therapies will work throughout the duration of the disease.

Specifically, it means that remyelination therapies do not need to be based on stem cell transplantation since the stem cells already present in the brain and spinal cord can be made to regenerate myelin - regardless of the patient's age."

MS affects approximately 100,000 people in the United Kingdom, 400,000 in the United States and several million worldwide. Symptoms of the disease can include the loss of physical skills, sensation, vision, bladder control, and intellectual abilities.


More information: The paper 'Rejuvenation of regeneration in the aging central nervous system' will be published in the 06 January edition of Cell Stem Cell.

Fear boosts activation of young, immature brain cells

Fear burns memories into our brain, and new research by University of California, Berkeley, neuroscientists explains how.

Scientists have long known that fear and other highly emotional experiences lead to incredibly strong memories.

In a study appearing online today (Tuesday, June 14) in advance of publication in the journal Molecular Psychiatry, UC Berkeley’s Daniela Kaufer and colleagues report a new way for emotions to affect memory: The brain’s emotional center, the amygdala, induces the hippocampus, a relay hub for memory, to generate new neurons.

In a fearful situation, these newborn neurons get activated by the amygdala and may provide a “blank slate” to strongly imprint the new fearful memory, she said. In evolutionary terms, it means new neurons are likely helping you to remember the lion that nearly killed you.

“We remember emotional events much more strongly than daily experiences, and for a long time we have known that connections between the amygdala and hippocampus help to encode this emotional information,” said Kaufer, an assistant professor of integrative biology and a member of UC Berkeley’s Wills Neuroscience Institute.

“Our research shows that amygdala input actually pushes the hippocampus to make new neurons from a unique population of neural stem cells. This provides completely new cells that get activated in response to emotional input.”

The finding has implications for post traumatic stress disorder (PTSD) and other problems caused by faulty regulation of emotional memory.

“Many affective disorders involve disordered emotional memories like PTSD, depression and anxiety. We think that newborn neurons may play a role in creating these emotional memories,” she said.

The finding comes a year after brain researcher Fred Gage at the Salk Institute for Biological Studies in La Jolla, Calif., showed that the formation of new memories is associated with increased activation of two-week-old newborn nerve cells in the hippocampus that are derived from adult neural stem cells.

Adult stem cells appear to differentiate continually into new nerve cells – nearly 100 each day – yet half of those newborn neurons are slated for death within four weeks after their birth.

If they are highly activated, however – such as in learning new complex information – many more of them will survive and presumably help in establishing new memories in the brain.

Kaufer, who conducts research on the effects of stress on the brain, knew that many types of positive and negative experiences, such as exercise and stress, affect the rate of neurogenesis in the hippocampus.

Along with graduate students Elizabeth Kirby, the lead author of the study, and Aaron Friedman, she was intrigued by the idea that emotions might affect neurogenesis in the hippocampus, since the brain’s clearinghouse for emotions, the amygdala, is connected to the hippocampus via multiple neural circuits.

To test this, Kirby focused on the basolateral amygdala, the region of the almond-shaped structure that handles negative emotions, including stress, anxiety and fear.

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Breakthrough, nerve connections are regenerated after spinal cord injury

Researchers for the first time have induced robust regeneration of nerve connections that control voluntary movement after spinal cord injury, showing the potential for new therapeutic approaches to paralysis and other motor function impairments.

In a study on rodents, the UC Irvine, UC San Diego and Harvard University team achieved this breakthrough by turning back the developmental clock in a molecular pathway critical for the growth of corticospinal tract nerve connections.

They did this by deleting an enzyme called PTEN (a phosphatase and tensin homolog), which controls a molecular pathway called mTOR that is a key regulator of cell growth. PTEN activity is low early during development, allowing cell proliferation. PTEN then turns on when growth is completed, inhibiting mTOR and precluding any ability to regenerate.

Trying to find a way to restore early-developmental-stage cell growth in injured tissue, Zhigang He, a senior neurology researcher at Children’s Hospital Boston and Harvard Medical School, first showed in a 2008 study that blocking PTEN in mice enabled the regeneration of connections from the eye to the brain after optic nerve damage.

He then partnered with Oswald Steward of UCI and Binhai Zheng of UCSD to see if the same approach could promote nerve regeneration in injured spinal cord sites. Results of their study appear online in Nature Neuroscience.

“Until now, such robust nerve regeneration has been impossible in the spinal cord,” said Steward, anatomy & neurobiology professor and director of the Reeve-Irvine Research Center at UCI. “Paralysis and loss of function from spinal cord injury has been considered untreatable, but our discovery points the way toward a potential therapy to induce regeneration of nerve connections following spinal cord injury in people.”