̽��ֱ�� of Cambridge - UK Dementia Research Institute

Glaucoma drug shows promise against neurodegenerative diseases, animal studies suggest

cjb250 — Thu, 31 Oct 2024 10:00:09 +0000

Researchers in the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge screened more than 1,400 clinically-approved drug compounds using zebrafish genetically engineered to make them mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors – of which the glaucoma drug methazolamide is one – clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Tauopathies are neurodegenerative diseases characterised by the build-up in the brain of tau protein ‘aggregates’ within nerve cells. These include forms of dementia, Pick's disease and progressive supranuclear palsy, where tau is believed to be the primary disease driver, and Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head trauma, as has been reported in football and rugby players), where tau build-up is one consequence of disease but results in degeneration of brain tissue.

There has been little progress in finding effective drugs to treat these conditions. One option is to repurpose existing drugs. However, drug screening – where compounds are tested against disease models – usually takes place in cell cultures, but these do not capture many of the characteristics of tau build-up in a living organism.

To work around this, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish grow to maturity and are able to breed within two to three months and produce large numbers of offspring. Using genetic manipulation, it is possible to mimic human diseases as many genes responsible for human diseases often have equivalents in the zebrafish.

In a study published today in Nature Chemical Biology, Professor David Rubinsztein, Dr Angeleen Fleming and colleagues modelled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for other diseases.

Dr Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, joint first author, said: “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms. They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice.”

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase – which is important for regulating acidity levels in cells – helped the cell rid itself of the tau protein build-up. It did this by causing the lysosomes – the ‘cell’s incinerators’ – to move to the surface of the cell, where they fused with the cell membrane and ‘spat out’ the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain, they found that those treated with the drug performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysis of the mouse brains showed that they indeed had fewer tau aggregates, and consequently a lesser reduction in brain cells, compared with the untreated mice.

Fellow joint author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were excited to see in our mouse studies that methazolamide reduces levels of tau in the brain and protects against its further build-up. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

Professor Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge, said: “Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. Although we’ve only looked at its effects in zebrafish and mice, so it is still early days, we at least know about this drug’s safety profile in patients. This will enable us to move to clinical trials much faster than we might normally expect if we were starting from scratch with an unknown drug compound.

“This shows how we can use zebrafish to test whether existing drugs might be repurposed to tackle different diseases, potentially speeding up significantly the drug discovery process.”

̽��ֱ��team hopes to test methazolamide on different disease models, including more common diseases characterised by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

̽��ֱ��research was supported by the UK Dementia Research Institute (through UK DRI Ltd, principally funded through the Medical Research Council), Tau Consortium and Wellcome.

Reference
Lopez, A & Siddiqi, FH et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; DOI: 10.1038/s41589-024-01762-7

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the build-up in the brain of the protein tau, which causes various forms of dementia and is implicated in Alzheimer’s disease.

Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms

Ana Lopez Ramirez

Kuznetsov_Peter

Zebrafish

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Scientists identify genes linked to DNA damage and human disease

cjb250 — Fri, 16 Feb 2024 10:17:07 +0000

̽��ֱ��work, published in Nature, provides insights into cancer progression and neurodegenerative diseases as well as a potential therapeutic avenue in the form of a protein inhibitor.

̽��ֱ��genome contains all the genes and genetic material within an organism's cells. When the genome is stable, cells can accurately replicate and divide, passing on correct genetic information to the next generation of cells. Despite its significance, little is understood about the genetic factors governing genome stability, protection, repair, and the prevention of DNA damage.

In this new study, researchers from the UK Dementia Research Institute, at the ̽��ֱ�� of Cambridge, and the Wellcome Sanger Institute set out to better understand the biology of cellular health and identify genes key to maintaining genome stability.

Using a set of genetically modified mouse lines, the team identified 145 genes that play key roles in either increasing or decreasing the formation of abnormal micronuclei structures. These structures indicate genomic instability and DNA damage, and are common hallmarks of ageing and diseases.

̽��ֱ��most dramatic increases in genomic instability were seen when the researchers knocked out the gene DSCC1, increasing abnormal micronuclei formation five-fold. Mice lacking this gene mirrored characteristics akin to human patients with a number of rare genetic disorders, further emphasising the relevance of this research to human health.

Using CRISPR screening, researchers showed this effect triggered by DSCC1 loss could be partially reversed through inhibiting protein SIRT1. This offers a highly promising avenue for the development of new therapies.

̽��ֱ��findings help shed light on genetic factors influencing the health of human genomes over a lifespan and disease development.

Professor Gabriel Balmus, senior author of the study at the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, formerly at the Wellcome Sanger Institute, said: “Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes, with the goal of improving outcomes and the overall quality of life for individuals across various conditions.”

Dr David Adams, first author of the study at the Wellcome Sanger Institute, said: “Genomic stability is central to the health of cells, influencing a spectrum of diseases from cancer to neurodegeneration, yet this has been a relatively underexplored area of research. This work, of 15 years in the making, exemplifies what can be learned from large-scale, unbiased genetic screening. ̽��ֱ��145 identified genes, especially those tied to human disease, offer promising targets for developing new therapies for genome instability-driven diseases like cancer and neurodevelopmental disorders.”

This research was supported by Wellcome and the UK Dementia Research Institute.

Reference
Adams, DJ et al. Genetic determinants of micronucleus formation in vivo. Nature; 14 Feb 2024; DOI: 10.1038/s41586-023-07009-0

Adapted from a press release from the Wellcome Sanger Institute.

Cambridge scientists have identified more than one hundred key genes linked to DNA damage through systematic screening of nearly 1,000 genetically modified mouse lines.

Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes

Gabriel Balmus

qimono

DNA puzzle

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HIV drug helps protect against build-up of dementia-related proteins in mouse brains

cjb250 — Wed, 26 Apr 2023 15:00:46 +0000

A common characteristic of neurodegenerative diseases such as Huntington’s disease and various forms of dementia is the build-up in the brain of clusters – known as aggregates – of misfolded proteins, such as huntingtin and tau. These aggregates lead to the degradation and eventual death of brain cells and the onset of symptoms.

One method that our bodies use to rid themselves of toxic materials is autophagy, or ‘self-eating’, a process whereby cells ‘eat’ the unwanted material, break it down and discard it. But this mechanism does not work properly in neurodegenerative diseases, meaning that the body is no longer able to get rid of the misfolded proteins.

In a study published today in Neuron, a team from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge has identified a process that causes autophagy not to work properly in the brains of mouse models of Huntington’s disease and a form of dementia – and importantly, has identified a drug that helps restore this vital function.

̽��ֱ��team carried out their research using mice that had been genetically-altered to develop forms of Huntington’s disease or a type of dementia characterised by the build-up of the tau protein.

̽��ֱ��brain and central nervous system have their own specialist immune cells, known as microglia, which should protect against unwanted and toxic materials. In neurodegenerative diseases, the microglia kick into action, but in such a way as to impair the process of autophagy.

Using mice, the team showed that in neurodegenerative diseases, microglia release a suite of molecules which in turn activate a switch on the surface of cells. When activated, this switch – called CCR5 – impairs autophagy, and hence the ability of the brain to rid itself of the toxic proteins. These proteins then aggregate and begin to cause irreversible damage to the brain – and in fact, the toxic proteins also create a feedback loop, leading to increased activity of CCR5, enabling even faster build-up of the aggregates.

Professor David Rubinsztein from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “ ̽��ֱ��microglia begin releasing these chemicals long before any physical signs of the disease are apparent. This suggests – much as we expected – that if we’re going to find effective treatments for diseases such as Huntington’s and dementia, these treatments will need to begin before an individual begins showing symptoms.”

When the researchers used mice bred to ‘knock out’ the action of CCR5, they found that these mice were protected against the build-up of misfolded huntingtin and tau, leading to fewer of the toxic aggregates in the brain when compared to control mice.

This discovery has led to clues to how this build-up could in future be slowed or prevented in humans. ̽��ֱ��CCR5 switch is not just exploited by neurodegenerative diseases – it is also used by HIV as a ‘doorway’ into our cells. In 2007, the US and European Union approved a drug known as maraviroc, which inhibits CCR5, as a treatment for HIV.

̽��ֱ��team used maraviroc to treat the Huntington’s disease mice, administering the drug for four weeks when the mice were two months old. When the researchers looked at the mice’s brains, they found a significant reduction in the number of huntingtin aggregates when compared to untreated mice. However, as Huntington’s disease only manifests in mice as mild symptoms by 12 weeks even without treatment, it was too early to see whether the drug would make an impact on the mice’s symptoms.

̽��ֱ��same effect was observed in the dementia mice. In these mice, not only did the drug reduce the amount of tau aggregates compared to untreated mice, but it also slowed down the loss of brain cells. ̽��ֱ��treated mice performed better than untreated mice at an object recognition test, suggesting that the drug slowed down memory loss.

Professor Rubinsztein added: “We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted, potentially even with an existing, safe treatment.

“Maraviroc may not itself turn out to be the magic bullet, but it shows a possible way forward. During the development of this drug as a HIV treatment, there were a number of other candidates that failed along the way because they were not effective against HIV. We may find that one of these works effectively in humans to prevent neurodegenerative diseases.”

̽��ֱ��research was supported by Alzheimer’s Research UK, the UK Dementia Research Institute, Alzheimer’s Society, Tau Consortium, Cambridge Centre for Parkinson-Plus, Wellcome and the European Union's Horizon 2020 research and innovation programme.

Reference
Festa, BP, Siddiqi, FH, & Jimenez-Sanchez, M, et al. Microglial-to-neuronal CCR5 signalling regulates autophagy in neurodegeneration. Neuron; 26 Apr 2023; DOI: 10.1016/j.neuron.2023.04.006

Cambridge scientists have shown how the brain’s ability to clear out toxic proteins is impaired in Huntington’s disease and other forms of dementia – and how, in a study in mice, a repurposed HIV drug was able to restore this function, helping prevent this dangerous build-up and slowing progression of the disease.

We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted

David Rubinsztein

Understanding Animal Research

Brown mouse

̽��ֱ��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.

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Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease

cjb250 — Fri, 24 Mar 2023 08:00:07 +0000

̽��ֱ��discovery is a step towards harnessing the protective effects of cooling the brain to treat patients with acute brain injury and even to prevent dementias, such as Alzheimer’s.

When the body cools down significantly, it increases its levels of RBM3, a molecule known as the cold shock protein – a phenomenon first observed in hibernating animals. It is thought that during hibernation, the protein helps protect the brain from damage and allows it to continue to form new connections.

In 2015, Professor Giovanna Mallucci and colleagues showed in mice that RBM3 can protect the brain against damage associated with build-up of misfolded proteins, which can lead to various forms of dementia, such as Alzheimer’s and Parkinson’s disease, and from prion diseases such as Creutzfeldt-Jakob Disease (CJD).

Induced hypothermia is used to treat patients in intensive care units – including newborn babies and traumatic brain injury patients – with the patients placed into a coma and their brains cooled to protect against damage. But this comes with associated risks, such as blood clotting and pneumonia. Could the cold shock protein be harnessed to treat patients without having to cool the body, offering a safer treatment for acute brain injury or a way of protecting the brain against dementia?

In research published in EMBO Molecular Medicine, scientists at the UK Dementia Research Institute, ̽��ֱ�� of Cambridge, and the Institute of Chemistry and Biochemistry, Freie Universität Berlin, studied whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice – and hence protect them.

̽��ֱ��team examined the gene that codes for production of the cold shock protein and found that it contains a key element which under normal conditions prevents its expression. Removing, or ‘dialling down’ this element using an ASO, results in a long-lasting boost to production of RBM3.

To test whether this approach could protect the brain, the researchers used mice infected with prions. Some of these mice were injected with a single dose of the ASO three weeks later, while the others were given a control treatment.

Twelve weeks after being administered the prions, those mice that had received the control treatment succumbed to prion disease and showed extensive loss of neurons in the hippocampus, an area of the brain important for memory.

̽��ֱ��story was very different for the mice that had received the ASO. At the same time as the other mice were succumbing to prion disease, the ASO-treated mice had levels of RBM3 twice as high as in the other mice. Seven of the eight ASO-treated mice showed extensive preservation of neurons in the hippocampus.

Professor Giovanna Mallucci, who led the work while at the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, said: “Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage to nerve cells in the brain during prion disease. Remarkably, we showed that just a single injection with the ASO was sufficient to provide long-lasting protection for these mice, preventing the inevitable progression of neurodegeneration.”

Professor Florian Heyd from Freie Universität Berlin added: “This approach offers the prospect of being able to protect against diseases such as Alzheimer’s and Parkinson’s disease, for which we have no reliable preventative treatments.

“We are still a long way off this stage as our work was in mice, but if we can safely use ASOs to boost production of the cold shock protein in humans, it might be possible to prevent dementia. We are already seeing ASOs being used to successfully treat spinal muscular atrophy and they have recently been licenced to treat motor neurone disease.”

If the findings can be replicated in humans, this approach could have major implications for the treatment of patients beyond neurodegeneration. These include acute brain injury from newborn babies with hypoxia through protecting the brain in heart surgery, stroke and head injury in adults who would otherwise be treated by therapeutic hypothermia.

Professor Mallucci is now based at the Alto Labs, Cambridge Institute of Science.

̽��ֱ��research was supported by core funding from the Freie Universität Berlin and by the UK Dementia Research Institute, which in turn is funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

Reference
Preußner, M et al. ASO targeting temperature-controlled RBM3 poison exon splicing prevents neurodegeneration in vivo. EMBO Molecular Medicine; 22 March 2023; DOI: 10.15252/emmm.202217157

Scientists in Cambridge and Berlin have used a form of gene therapy to increase levels of the so-called ‘cold shock protein’ in the brains of mice, protecting them against the potentially devastating impact of prion disease.

Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage nerve cells in the brain during prion disease

Giovanna Mallucci

Mika Ruusunen (Unsplash)

Cold water swimming

̽��ֱ��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.

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‘Stressed’ cells offer clues to eliminating build-up of toxic proteins in dementia

cjb250 — Fri, 06 May 2022 09:00:41 +0000

A characteristic of diseases such as Alzheimer’s and Parkinson’s – collectively known as neurodegenerative diseases – is the build-up of misfolded proteins. These proteins, such as amyloid and tau in Alzheimer’s disease, form ‘aggregates’ that can cause irreversible damage to nerve cells in the brain.

Protein folding is a normal process in the body, and in healthy individuals, cells carry out a form of quality control to ensure that proteins are correctly folded and that misfolded proteins are destroyed. But in neurodegenerative diseases, this system becomes impaired, with potentially devastating consequences.

As the global population ages, an increasing number of people are being diagnosed with dementia, making the search for effective drugs ever more urgent. However, progress has been slow, with no medicines yet available that can prevent or remove the build-up of aggregates.

In a study published today in Nature Communications, a team led by scientists at the UK Dementia Research Institute, ̽��ֱ�� of Cambridge, has identified a new mechanism that appears to reverse the build-up of aggregates, not by eliminating them completely, but rather by ‘refolding’ them.

“Just like when we get stressed by a heavy workload, so, too, cells can get ‘stressed’ if they’re called upon to produce a large amount of proteins,” explained Dr Edward Avezov from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge.

“There are many reasons why this might be, for example when they are producing antibodies in response to an infection. We focused on stressing a component of cells known as the endoplasmic reticulum, which is responsible for producing around a third of our proteins – and assumed that this stress might cause misfolding.”

̽��ֱ��endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It carries out a number of important functions, including the synthesis, folding, modification and transport of proteins needed on the surface or outside the cell. Dr Avezov and colleagues hypothesised that stressing the ER might lead to protein misfolding and aggregation by diminishing its ability to function correctly, leading to increased aggregation.

They were surprised to discover the opposite was true.

“We were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly,” said Dr Avezov.

“If we can find a way of awakening this mechanism without stressing the cells – which could cause more damage than good – then we might be able to find a way of treating some dementias.”

̽��ֱ��main component of this mechanism appears to be one of a class of proteins known as heat shock proteins (HSPs), more of which are made when cells are exposed to temperatures above their normal growth temperature, and in response to stress.

Dr Avezov speculates that this might help explain one of the more unusual observations within the field of dementia research. “There have been some studies recently of people in Scandinavian countries who regularly use saunas, suggesting that they may be at lower risk of developing dementia. One possible explanation for this is that this mild stress triggers a higher activity of HSPs, helping correct tangled proteins.”

One of the factors that has previous hindered this field of research has been the inability to visualise these processes in live cells. Working with teams from Pennsylvania State ̽��ֱ�� and the ̽��ֱ�� of Algarve, the team has developed a technique that allows them to detect protein misfolding in live cells. It relies on measuring light patterns of a glowing chemical over a scale of nanoseconds - one billionth of a second.

“It’s fascinating how measuring our probe’s fluorescence lifetime on the nanoseconds scale under a laser-powered microscope makes the otherwise invisible aggregates inside the cell obvious,” said Professor Eduardo Melo, one of the leading authors, from the ̽��ֱ�� of Algarve, Portugal.

̽��ֱ��research was supported by the UK Dementia Research Institute, which receives its funding from the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, as well as the Portuguese Foundation for Science and Technology.

Reference
Melo, EP, et al. Stress-induced protein disaggregation in the Endoplasmic Reticulum catalysed by BiP. Nature Comms; 6 May 2022; DOI: 10.1038/s41467-022-30238-2

It’s often said that a little stress can be good for you. Now scientists have shown that the same may be true for cells, uncovering a newly-discovered mechanism that might help prevent the build-up of tangles of proteins commonly seen in dementia.

We were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly

Edward Avezov

Jasmin Merdan

Taking care of elderly sick woman in wheelchair

̽��ֱ��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.

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New mechanism preventing toxic DNA lesions opens up therapeutic avenues for Huntington's disease

Anonymous — Wed, 01 Sep 2021 11:04:27 +0000

Researchers say the breakthrough study, published in Cell Reports, could lead to much needed therapies for the rare genetic disease, which is currently incurable.

Huntington's disease is a progressive and devastating neurodegenerative disorder that affects about 1 in 10,000 people in the UK.

̽��ֱ��disease is caused by the accumulation of toxic repetitive expansions of three DNA blocks called nucleotides (C, A and G) in the huntingtin (HTT) gene and is often termed a repeat expansion disorder. These CAG tri-nucleotide repeats are expanding by misuse of a cellular machinery that usually promotes DNA repair called ‘mismatch repair’. This overuse in mismatch repair drives Huntington's disease onset and progression.

In this study researchers investigated the role of FAN1 - a DNA repair protein that has been identified as a modifier of Huntington’s disease in several genetic studies; however, the mechanism affecting disease onset has remained elusive.

Using human cells and techniques that can read DNA repeat expansions, the researchers found that FAN1 can block the accumulation of the DNA mismatch repair factors to stop repeat expansion thus alleviating toxicity in cells derived from patients.

Co-lead authors Dr Rob Goold and PhD researcher Joseph Hamilton, both UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, said: “Evidence for DNA repair genes modifying Huntington's disease has been mounting for years. We show that new mechanisms are still waiting to be discovered, which is good news for patients.”

Medicines that could mimic or potentiate (increase the power of) FAN1 inhibition of mismatch repair would alter disease course. ̽��ֱ��team is now working with the biotechnology company Adrestia Therapeutics, based at the Babraham Research Campus near Cambridge, to translate these discoveries into therapies for substantial numbers of patients in the UK and worldwide.

Senior author of the study, Professor Sarah Tabrizi, director of the UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, stated: “Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable. We are now working with key pharma partners to try and develop therapies that target this mechanism and might one day reach the clinic.”

Joint senior author, Dr Gabriel Balmus from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, said: "There are currently more than fifty CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington's disease but to all the other repeat expansion disorders.”

Professor Steve Jackson, CSO and Interim CEO of Adrestia, said: “My colleagues and I are delighted to be working with Professor Tabrizi, Dr Balmus and the UK Dementia Research Institute to seek ways to translate their exciting science towards new medicines for Huntington's disease and potentially also other DNA-repeat expansion disorders.”

̽��ֱ��study was funded by the CHDI Foundation and UK Dementia Research Institute.

Reference
Goold, R et al. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease. Cell Reports; 31 August 2021; DOI: 10.1016/j.celrep.2021.109649

Adapted from a press release by UCL

A new mechanism that stops the progression of Huntington’s disease in cells has been identified by scientists at the ̽��ֱ�� of Cambridge and UCL, as part of their research groups at the UK Dementia Research Institute.

There are currently more than fifty CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington's disease but to all the other repeat expansion disorders

Gabriel Balmus

qimono

DNA jigsaw

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Cambridge Science Festival returns for milestone 25th year

Anonymous — Fri, 25 Jan 2019 15:48:27 +0000

Celebrating its 25th year, the Festival runs for two weeks from 11-24 March and explores the theme of ‘discoveries’. An impressive line-up of acclaimed scientists includes microscopist Professor Dame Pratibha Gai, Astronomer Royal Professor Lord Martin Rees, 2018 Nobel prize winner Sir Gregory Winter, geneticist Dr Giles Yeo, statistician Professor David Spiegelhalter, engineer Dr Hugh Hunt, marine biologist and author Helen Scales, THIS Institute Director Professor Mary Dixon-Woods, futurist Mark Stevenson, and science presenter Steve Mould.

̽��ֱ��full programme is teeming with events ranging from debates, talks, exhibitions, workshops and interactive activities to films, comedy and performances, held in lecture theatres, museums, cafes and galleries around Cambridge. There are events for all ages and most are free.
With so many events on offer, audiences will be spoilt for choice. Some of the biggest events in week one include:

Is technology making us miserable? (11 March). Virtually every interaction we have is mediated through technology. Despite being ‘always-on’, are we any better off? Are we better connected? Or is technology making us miserable?
Putting radioactivity in perspective (12 March). Following a renewal of electricity generated by nuclear power, Professors Ian Farnan and Gerry Thomas, Imperial College London, discuss radioactivity in the natural world and the outcomes of decades of study on the health effects of radiation. Could these research outcomes reset attitudes towards radiation and the risks?
̽��ֱ��universe of black holes (13 March). Christopher Reynolds, Plumian Professor of Astronomy, describes how future research into black holes may yet again change our view of reality.
̽��ֱ��long-term perspective of climate change (14 March). Professors Ulf Büntgen, Mike Hulme, Christine Lane, Hans W Linderholm, Clive Oppenheimer, Baskar Vira, and Paul J Krusic discuss how we investigate past climate and the challenges we face in applying this to the policy-making process.
Catalytic activation of renewable resources to make polymers and fuels (15 March). Professor Charlotte Williams, ̽��ֱ�� of Oxford, discusses the development of catalysts able to transform carbon dioxide into methanol, a process which may deliver more sustainable liquid transport fuels in the future.
Does the mother ever reject the fetus? (15 March). Professor Ashley Moffett discusses fetal rejection and explores new discoveries that show that there are multiple mechanisms to ensure there is a peaceful environment in the uterus, where the placenta is allowed to grow and develop to support the fetus.

Top picks for the second week include:

Cambridge gravity lecture: Sir Gregory Winter (18 March). Sir Gregory is a molecular biologist and 2018 Nobel Laureate best known for his work on developing technologies to make therapeutic monoclonal antibodies. His research has led to antibody therapies for cancer, rheumatoid arthritis and multiple sclerosis.
Discoveries leading to new treatments for dementia (18 March). Professor of Clinical Neurosciences and Associate Director of the UK Dementia Research Institute, Giovanna Mallucci discusses how new research leading to insights into dementia and degenerative brain diseases may lead to new treatments.
Improving quality and safety in healthcare (19 March). THIS Institute Director Professor Mary Dixon-Woods looks at the challenges to improving quality and safety in healthcare and considers why it’s so hard to answer the question: Does quality improvement actually improve quality? With Dr Fiona Godlee, Editor in Chief of ̽��ֱ��BMJ.
Immunology: the future of medicine? (19 March) Professor Clare Bryant and a panel of Cambridge immunologists discuss how understanding disease triggers may enable entirely new approaches to treating and potentially preventing disease.
Polar ocean: the dead end of plastic debris (19 March). An estimated 80% of all the litter in our oceans is plastic, and a significant concentration of plastics debris is found in both polar oceans. ̽��ֱ��impact of this debris on the sensitive polar ecosystem could be profound. Pelagic marine ecologist Dr Clara Manno, British Antarctic Survey, explores the current research and existing situation in the polar regions.
Reluctant futurist (19 March). Old models for healthcare, education, food production, energy supply and government are creaking under the weight of modern challenges. Futurist Mark Stevenson looks at the next 30 years and asks, how can we re-invent ourselves for the future?
Adolescent mental health: resilience after childhood adversity (20 March). Adolescence is characterised by huge physiological changes as well as a rapid rise in mental health disorders. Around 45% of adolescent mental health problems are caused by childhood difficulties but fortunately not all who experience difficulties develop mental health disorders. Dr Anne-Laura van Harmelen discusses mechanisms that may help adolescents with a history of childhood difficulty to become more resilient.
Making algorithms trustworthy (21 March). Increasingly, algorithms are being used to make judgements about sensitive parts of our lives. How do we check how their conclusions were arrived at, and if they are valid and fair? Professor David Spiegelhalter looks at efforts to make algorithms transparent and trustworthy, using systems that make predictions for people with cancer as an example.
On the future: prospects for humanity (22 March). Professor Lord Martin Rees argues that humanity’s prospects on Earth and in space depend on our taking a different approach to planning for tomorrow.

This year’s Cambridge Science Festival also celebrates significant milestones in science, including the 200th anniversary of Cambridge Philosophical Society, Cambridge’s oldest scientific society, and 150 years since the publication of the modern Periodic Table.

Speaking ahead of the Festival, Dr Lucinda Spokes, Festival Manager, said: “We are tremendously proud of this year’s programme due to the variety of events and the calibre of our speakers from a range of institutions and industries.

“Alongside the meatier topics we have an array of events for all ages and interests across both weekends. We have everything from the science of perfumery and how your mood affects your taste, to a science version of 'Would I Lie to You?'

“One of my personal top picks are the open days at the various institutes and departments based at the West Cambridge site on Saturday 23 March. As always, the site is hosting some truly fascinating events, everything from the future of construction and how to make Alexa smarter, to how nanotechnology is opening up new routes in healthcare, and state-of-the-art approaches to low-cost solar energy and high-efficiency lighting solutions.

“A Festival of this magnitude would not be possible without the help from many people; we thank all our scientists, supporters, partners and sponsors, without whom the Festival would not happen. Most of all, we thank the audiences – there are more than 60,000 visits to the Festival events every year. We very much look forward to welcoming everyone from all ages to join us in March to explore the fabulous world of science.”

You can download the full programme here.

Bookings open on Monday 11 February at 11am.

This year’s Festival sponsors and partners are Cambridge ̽��ֱ�� Press, AstraZeneca, MedImmune, Illumina, TTP Group, Science AAAS, Anglia Ruskin ̽��ֱ��, Astex Pharmaceuticals, Cambridge Science Centre, Cambridge Junction, IET, Hills Road 6th Form College, British Science Week, Cambridge ̽��ֱ�� Health Partners, Cambridge Academy for Science and Technology, and Walters Kundert Charitable Trust. Media Partners: BBC Radio Cambridgeshire and Cambridge Independent.

̽��ֱ��2019 Cambridge Science Festival is set to host more than 350 events as it explores a range of issues that affect today’s world, from challenges around climate change policy, improving safety and quality in healthcare, and adolescent mental health, to looking at what the next 25 years holds for us and whether quantum computers can change the world.

We have everything from the science of perfumery and how your mood affects your taste, to a science version of 'Would I Lie to You?'

Dr Lucinda Spokes

Yes