̽��ֱ�� of Cambridge - multiple sclerosis (MS)

Ancient DNA reveals reason for high MS and Alzheimer's rates in Europe

jg533 — Wed, 10 Jan 2024 16:06:31 +0000

Researchers have created the world’s largest ancient human gene bank, and used it to map the historical spread of genes – and diseases – over time as populations migrated.

Early-stage stem cell therapy trial shows promise for treating progressive MS

cjb250 — Mon, 27 Nov 2023 16:00:22 +0000

̽��ֱ��study, led by scientists at the ̽��ֱ�� of Cambridge, ̽��ֱ�� of Milan Bicocca and Hospital Casa Sollievo della Sofferenza (Italy), is a step towards developing an advanced cell therapy treatment for progressive MS.

Over 2 million people live with MS worldwide, and while treatments exist that can reduce the severity and frequency of relapses, two-thirds of MS patients still transition into a debilitating secondary progressive phase of disease within 25-30 years of diagnosis, where disability grows steadily worse.

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord.

Key immune cells involved in this process are macrophages (literally ‘big eaters’), which ordinarily attack and rid the body of unwanted intruders. A particular type of macrophage known as a microglial cell is found throughout the brain and spinal cord. In progressive forms of MS, they attack the central nervous system (CNS), causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that stem cell therapies might help ameliorate this damage. These involve the transplantation of stem cells, the body’s ‘master cells’, which can be programmed to develop into almost any type of cell within the body.

Previous work from the Cambridge team has shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, can help reduce inflammation and may be able to help repair damage caused by MS.

Now, in research published in the Cell Stem Cell, scientists have completed a first-in-human, early-stage clinical trial that involved injecting neural stem cells directly into the brains of 15 patients with secondary MS recruited from two hospitals in Italy. ̽��ֱ��trial was conducted by teams at the ̽��ֱ�� of Cambridge, Milan Bicocca and the Hospitals Casa Sollievo della Sofferenza and S. Maria Terni (IT) and Ente Ospedaliero Cantonale (Lugano, Switzerland) and the ̽��ֱ�� of Colorado (USA).

̽��ֱ��stem cells were derived from cells taken from brain tissue from a single, miscarried foetal donor. ̽��ֱ��Italian team had previously shown that it would be possible to produce a virtually limitless supply of these stem cells from a single donor – and in future it may be possible to derive these cells directly from the patient – helping to overcome practical problems associated with the use of allogeneic foetal tissue.

̽��ֱ��team followed the patients over 12 months, during which time they observed no treatment-related deaths or serious adverse events. While some side-effects were observed, all were either temporary or reversible.

All the patients showed high levels of disability at the start of the trial – most required a wheelchair, for example – but during the 12 month follow up period none showed any increase in disability or a worsening of symptoms. None of the patients reported symptoms that suggested a relapse and nor did their cognitive function worsen significantly during the study. Overall, say the researchers, this points to a substantial stability of the disease, without signs of progression, though the high levels of disability at the start of the trial make this difficult to confirm.

̽��ֱ��researchers assessed a subgroup of patients for changes in the volume of brain tissue associated with disease progression. They found that the larger the dose of injected stem cells, the smaller the reduction in this brain volume over time. They speculate that this may be because the stem cell transplant dampened inflammation.

̽��ֱ��team also looked for signs that the stem cells were having a neuroprotective effect – that is, protecting nerve cells from further damage. Their previous work showed how tweaking metabolism – how the body produces energy – can in turn reprogram microglia from ‘bad’ to ‘good’. In this new study, they looked at how the brain's metabolism changes after the treatment. They measured changes in the fluid around the brain and in the blood over time and found certain signs that are linked to how the brain processes fatty acids. These signs were connected to how well the treatment works and how the disease develops. ̽��ֱ��higher the dose of stem cells, the greater the levels of fatty acids, which also persisted over the 12-month period.

Professor Stefano Pluchino from the ̽��ֱ�� of Cambridge, who co-led the study, said: “We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS.

“We recognise that our study has limitations – it was only a small study and there may have been confounding effects from the immunosuppressant drugs, for example – but the fact that our treatment was safe and that its effects lasted over the 12 months of the trial means that we can proceed to the next stage of clinical trials.”

Co-leader Professor Angelo Vescovi from the ̽��ֱ�� of Milano-Bicocca said: “It has taken nearly three decades to translate the discovery of brain stem cells into this experimental therapeutic treatment This study will add to the increasing excitement in this field and pave the way to broader efficacy studies, soon to come.”

Caitlin Astbury, Research Communications Manager at the MS Society, says: “This is a really exciting study which builds on previous research funded by us. These results show that special stem cells injected into the brain were safe and well-tolerated by people with secondary progressive MS. They also suggest this treatment approach might even stabilise disability progression. We’ve known for some time that this method has the potential to help protect the brain from progression in MS.

“This was a very small, early-stage study and we need further clinical trials to find out if this treatment has a beneficial effect on the condition. But this is an encouraging step towards a new way of treating some people with MS.”

Reference
Leone, MA, Gelati, M & Profico, DC et al. Intracerebroventricular Transplantation of Foetal Allogeneic Neural Stem Cells in Patients with Secondary Progressive Multiple Sclerosis (hNSC-SPMS): a phase I dose escalation clinical trial. Cell Stem Cell; 27 Nov 2023; DOI: 10.1016/j.stem.2023.11.001

An international team has shown that the injection of a type of stem cell into the brains of patients living with progressive multiple sclerosis (MS) is safe, well tolerated and has a long-lasting effect that appears to protect the brain from further damage.

I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS

Stefano Pluchino

Early-stage stem cell therapy trial shows promise for treating progressive MS

eyecrave productions (Getty Images)

Mature Adult Female with Disability

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Scientists identify first genetic marker for MS severity

cjb250 — Wed, 28 Jun 2023 15:00:58 +0000

Multiple sclerosis (MS) is the result of the immune system mistakenly attacking the brain and the spinal cord, resulting in symptom flares known as relapses as well as longer-term degeneration, known as progression. Despite the development of effective treatments for relapses, some of which were pioneered at the ̽��ֱ�� of Cambridge, none can reliably prevent the accumulation of disability.

In findings published today in Nature, an international collaboration of researchers report a genetic variant that increases disease severity, providing the first real progress in understanding and eventually fighting this aspect of MS.

̽��ֱ��work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF (USA) and the ̽��ֱ�� of Cambridge (UK).

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Professor Sergio Baranzini at UCSF, co-senior author of the study.

“Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression,” said Professor Stephen Sawcer from the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, the other co-senior author of the study.

To address the mystery of MS severity, two large MS research consortia joined forces: ̽��ֱ��International Multiple Sclerosis Genetics Consortium (IMSGC) and ̽��ֱ��MultipleMS Consortium. This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes.

Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease. But, explained Baranzini, “these risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons.”

̽��ֱ��two consortia combined data from over 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to carefully link genetic variants to particular traits. In this case, the traits of interest were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability.

After sifting through more than seven million genetic variants, the scientists found one that was associated with faster disease progression. ̽��ֱ��variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. ̽��ֱ��first is involved in repairing damaged cells, and the second helps to control viral infections. ̽��ֱ��variant’s proximity to these genes suggests that they may be involved in disease progression.

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Dr Adil Harroud, lead author of the study and former postdoctoral researcher in the Baranzini Lab. “Our findings suggest that resilience and repair in the nervous system determine the course of MS progression and that we should focus on these parts of human biology for better therapies.”

̽��ֱ��findings give the field its first leads to address the nervous system component of MS.

̽��ֱ��team also used statistical methods known as 'Mendelian randomisation' to explore the importance of environmental effects and found that years of education and parental age reduced the severity of MS, while smoking worsened it. Finding correlation with these indirect measures of brain health further underlines the importance of resilience in determining the outcome of MS.

“Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience,” Sawcer said.

To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster.

Further work will be necessary to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. ̽��ֱ��researchers are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability in MS.

“This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS,” said Harroud.

Studying the genetics of multiple sclerosis has been a major theme of neurological research in Cambridge since the late 1980s. With others, members of the Department of Clinical Neurosciences have been closely involved in discovery of the vast majority of gene variants that increase susceptibility.

Professor Alastair Compston from the ̽��ֱ�� of Cambridge and a founding member of the IMSGC added: “Having been personally involved with the identification of susceptibility genes for multiple sclerosis since the 1970s, it is a tribute to those within IMSGC who led this project that fully independent risk variants for progression have now been discovered.

“Once more, the work illustrates the benefits of international collaboration for advancing the understanding of disease mechanisms in multiple sclerosis and other medical conditions”.

This work was supported in part by funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the European Union’s Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.

Reference
International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature; 28 June 2023 DOI: 10.1038/s41586-023-06250-x

A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression, which can rob patients of their mobility and independence over time.

Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience

Stephen Sawcer

eyecrave productions (Getty Images)

Woman with multiple sclerosis

Yes

Cambridge scientists reverse ageing process in rat brain stem cells

Anonymous — Wed, 14 Aug 2019 17:01:45 +0000

̽��ֱ��results, published today in Nature, have far-reaching implications for how we understand the ageing process, and how we might develop much-needed treatments for age-related brain diseases.

As our bodies age, our muscles and joints can become stiff, making everyday movements more difficult. This study shows the same is true in our brains, and that age-related brain stiffening has a significant impact on the function of brain stem cells.

A multi-disciplinary research team, based at the Wellcome-MRC Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge, studied young and old rat brains to understand the impact of age-related brain stiffening on the function of oligodendrocyte progenitor cells (OPCs). These cells are a type of brain stem cell important for maintaining normal brain function, and for the regeneration of myelin – the fatty sheath that surrounds our nerves, which is damaged in multiple sclerosis (MS). ̽��ֱ��effects of age on these cells contributes to MS, but their function also declines with age in healthy people.

To determine whether the loss of function in aged OPCs was reversible, the researchers transplanted older OPCs from aged rats into the soft, spongy brains of younger animals. Remarkably, the older brain cells were rejuvenated, and began to behave like the younger, more vigorous cells.

To study this further, the researchers developed new materials in the lab with varying degrees of stiffness, and used these to grow and study the rat brain stem cells in a controlled environment. ̽��ֱ��materials were engineered to have a similar softness to either young or old brains.

To fully understand how brain softness and stiffness influences cell behavior, the researchers investigated Piezo1 – a protein found on the cell surface, which informs the cell whether the surrounding environment is soft or stiff.

Dr Kevin Chalut, who co-led the research, said: “We were fascinated to see that when we grew young, functioning rat brain stem cells on the stiff material, the cells became dysfunctional and lost their ability to regenerate, and in fact began to function like aged cells. What was especially interesting, however, was that when the old brain cells were grown on the soft material, they began to function like young cells – in other words, they were rejuvenated.”

“When we removed Piezo1 from the surface of aged brain stem cells, we were able to trick the cells into perceiving a soft surrounding environment, even when they were growing on the stiff material,” explained Professor Robin Franklin, who co-led the research with Dr Chalut. “What’s more, we were able to delete Piezo1 in the OPCs within the aged rat brains, which lead to the cells becoming rejuvenated and once again able to assume their normal regenerative function.”

Dr Susan Kohlhaas, Director of Research at the MS Society, who part funded the research, said: “MS is relentless, painful, and disabling, and treatments that can slow and prevent the accumulation of disability over time are desperately needed. ̽��ֱ��Cambridge team’s discoveries on how brain stem cells age and how this process might be reversed have important implications for future treatment, because it gives us a new target to address issues associated with aging and MS, including how to potentially regain lost function in the brain.”

This research was supported by the European Research Council, MS Society, Biotechnology and Biological Sciences Research Council, ̽��ֱ��Adelson Medical Research Foundation, Medical Research Council and Wellcome.

Niche stiffness underlies the ageing of central nervous system progenitor cells, M. Segel, B. Neumann, M. Hill, I. Weber, C. Viscomi, C. Zhao, A. Young, C. Agley, A. Thompson, G. Gonzalez, A. Sharma, S. Holmqvist, D. Rowitch, K. Franze, R. Franklin and K. Chalut is published in Nature.

New research reveals how increasing brain stiffness as we age causes brain stem cell dysfunction, and demonstrates new ways to reverse older stem cells to a younger, healthier state.

...when the old brain cells were grown on the soft material, they began to function like young cells – in other words, they were rejuvenated

Kevin Chalut

Mikey Segel

Aged rat brain stem cells grown on a soft surface (right) show more healthy, vigorous growth than similar aged brain stem cells grown on a stiff surface (left). ̽��ֱ��red marker shows brain stem cells, and the green marker indicates cell proliferation.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Study in mice suggests personalised stem cell treatment may offer relief for progressive MS

cjb250 — Thu, 22 Feb 2018 17:00:03 +0000

̽��ֱ��study, led by researchers at the ̽��ֱ�� of Cambridge, is a step towards developing personalised treatments based on a patient’s own skin cells for diseases of the central nervous system (CNS).

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord. Symptoms are unpredictable and include problems with mobility and balance, pain, and severe fatigue.

Key immune cells involved in causing this damage are macrophages (literally ‘big eaters’), which ordinarily serve to attack and rid the body of unwanted intruders. A particular type of macrophage known as microglia are found throughout the brain and spinal cord – in progressive forms of MS, they attack the CNS, causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that diseases of the CNS may be improved by the use of stem cell therapies. Stem cells are the body’s ‘master cells’, which can develop into almost any type of cell within the body. Previous work from the Cambridge team has shown that transplanting neural stem cells (NSCs) – stem cells that are part-way to developing into nerve cells – reduces inflammation and can help the injured CNS heal.

However, even if such a therapy could be developed, it would be hindered by the fact that such NSCs are sourced from embryos and therefore cannot be obtained in large enough quantities. Also, there is a risk that the body will see them as an alien invader, triggering an immune response to destroy them.

A possible solution to this problem would be the use of so-called ‘induced neural stem cells (iNSCs)’ – these cells can be generated by taking an adult’s skin cells and ‘re-programming’ them back to become neural stem cells. As these iNSCs would be the patient’s own, they are less likely to trigger an immune response.

Now, in research published in the journal Cell Stem Cell, researchers at the ̽��ֱ�� of Cambridge have shown that iNSCs may be a viable option to repairing some of the damage caused by MS.

Using mice that had been manipulated to develop MS, the researchers discovered that chronic MS leads to significantly increased levels of succinate, a small metabolite that sends signals to macrophages and microglia, tricking them into causing inflammation, but only in cerebrospinal fluid, not in the peripheral blood.

Transplanting NSCs and iNSCs directly into the cerebrospinal fluid reduces the amount of succinate, reprogramming the macrophages and microglia – in essence, turning ‘bad’ immune cells ‘good’. This leads to a decrease in inflammation and subsequent secondary damage to the brain and spinal cord.

“Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS,” says Dr Stefano Pluchino, lead author of the study from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge.

“This is particularly promising as these cells should be more readily obtainable than conventional neural stem cells and would not carry the risk of an adverse immune response.”

̽��ֱ��research team was led by Dr Pluchino, together with Dr Christian Frezza from the MRC Cancer Unit at the ̽��ֱ�� of Cambridge, and brought together researchers from several university departments.

Dr Luca Peruzzotti-Jametti, the first author of the study and a Wellcome Trust Research Training Fellow, says: “We made this discovery by bringing together researchers from diverse fields including regenerative medicine, cancer, mitochondrial biology, inflammation and stroke and cellular reprogramming. Without this multidisciplinary collaboration, many of these insights would not have been possible."

̽��ֱ��research was funded by Wellcome, European Research Council, Medical Research Council, Italian Multiple Sclerosis Association, Congressionally-Directed Medical Research Programs, the Evelyn Trust and the Bascule Charitable Trust.

Reference
Peruzzotti-Jametti, L et al. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell; 2018; 22: 1-14; DOI: 10.1016/j.stem.2018.01.20

Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis (MS).

Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS

Luca Peruzzotti-Jametti

Andrew c

Neuron with oligodendrocyte and myelin sheath (edited)

Researcher profile: Dr Luca Peruzzotti-Jametti

It isn’t every day that you find yourself invited to play croquet with a Nobel laureate, but then Cambridge isn’t every university, as Dr Luca Peruzzotti-Jametti discovered when he was fortunate enough to be invited to the house of Professor Sir John Gurdon.

“It was an honour meet a Nobel laureate who has influenced so much my studies and meet the man behind the science,” he says. “I was moved by how kind he is and extremely impressed by his endless passion for science.”

Dr Peruzzotti-Jametti began his career studying medicine at the ̽��ֱ�� Vita-Salute San Raffaele, Milan. His career took him across Europe, to Switzerland, Denmark, Sweden and now to Cambridge. After completing a PhD in Clinical Neurosciences here he is now a Wellcome Trust Research Training fellow.

His work focuses on multiple sclerosis (MS), an autoimmune disease that affects around 100,000 people in the UK alone. Despite having several therapies to help during the initial (or ‘relapsing remitting’) phase of MS, the majority of people with MS will develop a chronic worsening of disability within 15 years after diagnosis. This late form of MS is called secondary progressive, and differently from relapsing remitting MS, it does not have any effective treatment.

“My research sets out to understand how progression works in MS by studying how inflammation is maintained in the brains of patients, and to develop new treatments aimed at preventing disease progression,” he explains. Among his approaches is the use of neural stem cells and induced neural stem cells, as in the above study. “My hope is that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS.”

Dr Peruzzotti-Jametti is based on the Cambridge Biomedical Campus where he works closely with clinicians at Addenbrooke’s Hospital and with basic scientists, a community he describes as “vibrant”.

“Cambridge has been the best place to do my research due to the incredible concentration of scientists who pursue novel therapeutic approaches using cutting-edge technologies,” he says. “I am very thankful for the support I received in the past years from top notch scientists. Being in Cambridge has also helped me competing for major funding sources and my work could have not been possible without the support of the Wellcome Trust.

“I wish to continue working in this exceptional environment where so many minds and efforts are put together in a joint cause for the benefit of those who suffer.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Leprosy turns the immune system against itself, study finds

cjb250 — Wed, 23 Aug 2017 08:33:57 +0000

Leprosy is an infectious disease that affects the skin and peripheral nerves and is caused by Mycobacterium leprae and, less commonly, Mycobacterium lepromatosis. According to the World Health Organization, there has been a dramatic decrease in the global disease burden in the past few decades: from 5.2 million people with leprosy in 1985 to 176,176 at the end of 2015.

Despite the disease having been known about for thousands of years – many people will have first heard about it through references in the Bible – very little is understood about its biology. This is in part because the bacteria are difficult to grow in culture and there are no good animal models: M. leprae can grow in the footpads of mice, but do not cause nerve damage; the disease causes nerve damage in armadillos, but these animals are rarely used in research.

Now, an international team led by researchers at the ̽��ֱ�� of Cambridge, UK, and the ̽��ֱ�� of Washington, the ̽��ֱ�� of California Los Angeles and Harvard ̽��ֱ��, USA, have used a new animal model, the zebrafish, to show for the first time how M. leprae damage nerves by infiltrating the very cells that are meant to protect us. Zebrafish are already used to study another species of mycobacteria, to help understand tuberculosis (TB).

Scientists have previously shown that the nerve damage in leprosy is caused by a stripping away of the protective insulation, the myelin sheath, that protects nerve fibres, but it was thought that this process occurred because the bacteria got inside Schwann cells, specialist cells that produce myelin.

In new research published today in the journal Cell, researchers used zebrafish that had been genetically modified so that their myelin is fluorescent green; young zebrafish are themselves transparent, and so the researchers could more easily observe what was happening to the nerve cells. When they injected bacteria close to the nerve cells of the zebrafish, they observed that the bacteria settled on the nerve, developing donut-like ‘bubbles’ of myelin that had dissociated from the myelin sheath.

When they examined these bubbles more closely, they found that they were caused by M. leprae bacteria inside of macrophages – literally ‘big eaters’, immune cells that consume and destroy foreign bodies and unwanted material within the body. But, as is also often the case with TB, the M. leprae was consumed by the macrophages but not destroyed.

“These ‘Pac-Man’-like immune cells swallow the leprosy bacteria, but are not always able to destroy them,” explains Professor Lalita Ramakrishnan from the Department of Medicine at the ̽��ֱ�� of Cambridge, whose lab is within the Medical Research Council’s Laboratory of Molecular Biology. “Instead, the macrophages – which should be moving up and down the nerve fibre repairing damage – slow down and settle in place, destroying the myelin sheath.”

Professor Ramakrishnan working with Dr Cressida Madigan, Professor Alvaro Sagasti, and other colleagues confirmed that this was the case by knocking out the macrophages and showing that when the bacteria sit directly on the nerves, they do not damage the myelin sheath.

̽��ֱ��team further demonstrated how this damage occurs. A molecule known as PGL-1 that sits on the surface of M. leprae ‘reprograms’ the macrophage, causing it to overproduce a potentially destructive form of the chemical nitric oxide that damages mitochondria, the ‘batteries’ that power nerves.

“ ̽��ֱ��leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry,” says Professor Ramakrishnan. “It then starts spewing out toxic chemicals. Not only does it stop repairing damage, but it creates more damage itself.”

“We know that the immune system can lead to nerve damage – and in particular to the myelin sheath – in other diseases, such as multiple sclerosis and Guillain–Barré syndrome,” says Dr Cressida Madigan from the ̽��ֱ�� of California, Los Angeles. “Our study appears to place leprosy in the same category of these diseases.”

̽��ֱ��researchers say it is too early to say whether this study will lead to new treatments. There are several drugs being tested that inhibit the production of nitric oxide, but, says Professor Ramakrishnan, the key may be to catch the disease at an early enough stage to prevent damage to the nerve cells.

“We need to be thinking about degeneration versus regeneration,” she says. “At the moment, leprosy can be treated by a combination of drugs. While these succeed in killing the bacteria, once the nerve damage has been done, it is currently irreversible. We would like to understand how to change that. In other words, are we able to prevent damage to nerve cells in the first place and can we additionally focus on repairing damaged nerve cells?”

̽��ֱ��research was funded by the National Institutes of Health, the Wellcome Trust, and the AP Giannini Foundation.

Reference
Madigan, CA et al. A Macrophage Response To Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage In Leprosy. Cell; 24 Aug 2017; DOI: 10.1016/j.cell.2017.07.030

Leprosy hijacks our immune system, turning an important repair mechanism into one that causes potentially irreparable damage to our nerve cells, according to new research that uses zebrafish to study the disease. As such, the disease may share common characteristics with conditions such as multiple sclerosis.

̽��ֱ��leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry

Lalita Ramakrishnan

Wellcome Library, London

Hand showing leprosy

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

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Attribution

Vitamin D could repair nerve damage in multiple sclerosis, study suggests

cjb250 — Mon, 07 Dec 2015 14:00:25 +0000

Researchers, from the MS Society Cambridge Centre for Myelin Repair, identified that the ‘vitamin D receptor’ protein pairs with an existing protein, called the RXR gamma receptor, already known to be involved in the repair of myelin, the protective sheath surrounding nerve fibres.

By adding vitamin D to brain stem cells where the proteins were present, they found the production rate of oligodendrocytes (myelin making cells) increased by 80%. When they blocked the vitamin D receptor to stop it from working, the RXR gamma protein alone was unable to stimulate the production of oligodendrocytes.

In MS, the body’s own immune system attacks and damages myelin, causing disruption to messages sent around the brain and spinal cord; symptoms are unpredictable and include problems with mobility and balance, pain, and severe fatigue. ̽��ֱ��body has a natural ability to repair myelin, but with age this becomes less effective.

Professor Robin Franklin from the MS Society Cambridge Centre for Myelin Repair and the Wellcome Trust-Medical Research Council Stem Cell Institute, who led the study, says: “For years scientists have been searching for a way to repair damage to myelin. So far, the majority of research on vitamin D has looked at its role in the cause of the disease. This work provides significant evidence that vitamin D is also involved in the regeneration of myelin once the disease has started. In the future we could see a myelin repair drug that works by targeting the vitamin D receptor.”

Dr Susan Kohlhaas, Head of Biomedical Research at the MS Society, said: “More than 100,000 people in the UK have multiple sclerosis and finding treatments that can slow, stop or reverse the worsening of disability is a priority for the MS Society. We’d now like to see more studies to understand whether taking vitamin D supplements could, in time, be an effective and safe treatment for people with MS.

She continued: “For now though, this is early stage research that’s been done in the laboratory and more work is needed before we know whether it would hold true in people with MS. It’s not a good idea, however, to be deficient in vitamin D and we’d encourage anybody who thinks they might be to speak to their GP.”

Following this research, scientists will need to understand more about the underlying biology of this receptor before considering how the vitamin D receptor could be safely and effectively targeted in future trials in people with MS.

Reference
Guzman de la Fuente, A et al. Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. Journal of Cell Biology; 7 Dec 2015

Adapted from a press release by the MS Society

A protein activated by vitamin D could be involved in repairing damage to myelin in people with multiple sclerosis (MS), according to new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��study, published today in the Journal of Cell Biology, offers significant evidence that vitamin D could be a possible treatment for MS in the future.

This work provides significant evidence that vitamin D is involved in the regeneration of myelin once the disease has started

Robin Franklin

Andrew c

Neuron with oligodendrocyte and myelin sheath (edited)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

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Attribution

Calling for help: damaged nerve cells communicate with stem cells

cjb250 — Tue, 06 Oct 2015 13:18:52 +0000

̽��ֱ��study, published today in the journal Nature Communications, may have significant implications for the development of future medicines for disorders that affect myelin sheath, the insulation that protects and insulates our nerve cells.

For our brain and central nervous system to work, electrical signals must travel quickly along nerve fibres. This is achieved by insulating the nerve fibres with a fatty substance called myelin. In diseases such as MS, the myelin sheath around nerve fibres is lost or damaged, causing physical and mental disability.

Stem cells – the body’s master cells, which can develop into almost any type of cell – can act as ‘first aid kits’, repairing damage to the body. In our nervous system, these stem cells are capable of producing new myelin, which, in the case of MS, for example, can help recover lost function. However, myelin repair often fails, leading to sustained disability. To understand why repair fails in disease, and to design novel ways of promoting myelin repair, researchers at the Wellcome Trust-Medical Research Council Stem Cell Institute at the ̽��ֱ�� of Cambridge studied how this repair process works.

When nerve fibres lose myelin, they stay active but conduct signals at much lower speed than healthy fibres. Using electrical recording techniques, a team of researchers led by Dr Thora Karadottir discovered that the damaged nerve fibres then form connections with stem cells. These connections are the same as those that connect synapses between different nerve fibres. These new synaptic connections enable the damaged fibres to communicate directly with the stem cells by releasing the glutamate, a chemical that the stem cells can sense via receptors. This communication is critical for directing the stem cells to produce new myelin – when the researchers inhibited either the nerve fibres’ activity, their ability to communicate, or the stem cells’ ability to sense the communication, the repair process fails.

“This is the first time that we’ve been able to show that damaged nerve fibres communicate with stem cells using synaptic connections – the same connections they use to ‘talk to’ other nerve cells,” says Dr Karadottir. “Armed with this new knowledge, we can start looking into ways to enhance this communication to promote myelin repair in disease.”

Dr Helene Gautier from the Department of Physiology, Development and Neuroscience, adds: "So far, the majority of the available treatments are only slowing down damage. Our research opens the possibility to enhance repair and potentially treat the most devastating forms of MS and demyelinated diseases."

Reference
Gautier, HOB et al. Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors. Nature Communications; 6 Oct 2015

Nerve cells damaged in diseases such as multiple sclerosis (MS), ‘talk’ to stem cells in the same way that they communicate with other nerve cells, calling out for ‘first aid’, according to new research from the ̽��ֱ�� of Cambridge.

This is the first time that we’ve been able to show that damaged nerve fibres communicate with stem cells using synaptic connections – the same connections they use to ‘talk to’ other nerve cells

Thora Karadottir

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First Aid Kit (cropped)

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