̽��ֱ�� of Cambridge - Cambridge Institute for Medical Research (CIMR)

Throwing a ‘spanner in the works’ of our cells’ machinery could help fight cancer, fatty liver disease… and hair loss

cjb250 — Fri, 18 Apr 2025 18:00:53 +0000

Scientists at the Medical Research Council (MRC) Mitochondrial Biology Unit, ̽��ֱ�� of Cambridge, have worked out the structure of this machine and shown how it operates like the lock on a canal to transport pyruvate – a molecule generated in the body from the breakdown of sugars – into our mitochondria.

Known as the mitochondrial pyruvate carrier, this molecular machine was first proposed to exist in 1971, but it has taken until now for scientists to visualise its structure at the atomic scale using cryo-electron microscopy, a technique used to magnify an image of an object to around 165,000 times its real size. Details are published today in Science Advances.

Dr Sotiria Tavoulari, a Senior Research Associate from the ̽��ֱ�� of Cambridge, who first determined the composition of this molecular machine, said: “Sugars in our diet provide energy for our bodies to function. When they are broken down inside our cells they produce pyruvate, but to get the most out of this molecule it needs to be transferred inside the cell’s powerhouses, the mitochondria. There, it helps increase 15-fold the energy produced in the form of the cellular fuel ATP.”

Maximilian Sichrovsky, a PhD student at Hughes Hall and joint first author of the study, said: “Getting pyruvate into our mitochondria sounds straightforward, but until now we haven’t been able to understand the mechanism of how this process occurs. Using state-of-the-art cryo-electron microscopy, we’ve been able to show not only what this transporter looks like, but exactly how it works. It’s an extremely important process, and understanding it could lead to new treatments for a range of different conditions.”

Mitochondria are surrounded by two membranes. ̽��ֱ��outer one is porous, and pyruvate can easily pass through, but the inner membrane is impermeable to pyruvate. To transport pyruvate into the mitochondrion, first an outer ‘gate’ of the carrier opens, allowing pyruvate to enter the carrier. This gate then closes, and the inner gate opens, allowing the molecule to pass through into the mitochondrion.

“It works like the locks on a canal but on the molecular scale,” said Professor Edmund Kunji from the MRC Mitochondrial Biology Unit, and a Fellow at Trinity Hall, Cambridge. “There, a gate opens at one end, allowing the boat to enter. It then closes and the gate at the opposite end opens to allow the boat smooth transit through.”

Because of its central role in controlling the way mitochondria operate to produce energy, this carrier is now recognised as a promising drug target for a range of conditions, including diabetes, fatty liver disease, Parkinson’s disease, specific cancers, and even hair loss.

Pyruvate is not the only energy source available to us. Our cells can also take their energy from fats stored in the body or from amino acids in proteins. Blocking the pyruvate carrier would force the body to look elsewhere for its fuel – creating opportunities to treat a number of diseases. In fatty liver disease, for example, blocking access to pyruvate entry into mitochondria could encourage the body to use potentially dangerous fat that has been stored in liver cells.

Likewise, there are certain tumour cells that rely on pyruvate metabolism, such as in some types of prostate cancer. These cancers tend to be very ‘hungry’, producing excess pyruvate transport carriers to ensure they can feed more. Blocking the carrier could then starve these cancer cells of the energy they need to survive, killing them.

Previous studies have also suggested that inhibiting the mitochondrial pyruvate carrier may reverse hair loss. Activation of human follicle cells, which are responsible for hair growth, relies on metabolism and, in particular, the generation of lactate. When the mitochondrial pyruvate carrier is blocked from entering the mitochondria in these cells, it is instead converted to lactate.

Professor Kunji said: “Drugs inhibiting the function of the carrier can remodel how mitochondria work, which can be beneficial in certain conditions. Electron microscopy allows us to visualise exactly how these drugs bind inside the carrier to jam it – a spanner in the works, you could say. This creates new opportunities for structure-based drug design in order to develop better, more targeted drugs. This will be a real game changer.”

̽��ֱ��research was supported by the Medical Research Council and was a collaboration with the groups of Professors Vanessa Leone at the Medical College of Wisconsin, Lucy Forrest at the National Institutes of Health, and Jan Steyaert at the Free ̽��ֱ�� of Brussels.

Reference

Sichrovsky, M, Lacabanne, D, Ruprecht, JJ & Rana, JJ et al. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier. Sci Adv; 18 Apr 2025; DOI: 10.1126/sciadv.adw1489

Fifty years since its discovery, scientists have finally worked out how a molecular machine found in mitochondria, the ‘powerhouses’ of our cells, allows us to make the fuel we need from sugars, a process vital to all life on Earth.

Drugs inhibiting the function of the carrier can remodel how mitochondria work, which can be beneficial in certain conditions

Edmund Kunji

bob_bosewell (Getty Images)

Bald young man, front view

̽��ֱ��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 – 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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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

Yes

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Public Domain

Rare disease research at Cambridge receives major boost with launch of two new centres

cjb250 — Mon, 22 Apr 2024 23:34:17 +0000

̽��ֱ��virtual centres, supported by the charity LifeArc, will focus on areas where there are significant unmet needs. They will tackle barriers that ordinarily prevent new tests and treatments reaching patients with rare diseases and speed up the delivery of rare disease treatment trials.

̽��ֱ��centres will bring together leading scientists and rare disease clinical specialists from across the UK for the first time, encouraging new collaborations across different research disciplines and providing improved access to facilities and training.

LifeArc Centre for Rare Mitochondrial Diseases

Professor Patrick Chinnery will lead the LifeArc Centre for Rare Mitochondrial Diseases, a national partnership with the Lily Foundation and Muscular Dystrophy UK, together with key partners at UCL, Newcastle ̽��ֱ�� and three other centres (Oxford, Birmingham and Manchester).

Mitochondrial diseases are genetic disorders affecting 1 in 5,000 people. They often cause progressive damage to the brain, eyes, muscles, heart and liver, leading to severe disability and a shorter life. There is currently have no cure for most conditions, however, new opportunities to treat mitochondrial diseases have been identified in the last five years, meaning that it’s a critical time for research development. ̽��ֱ��£7.5M centre will establish a national platform that will connect patient groups, knowledge and infrastructure in order to accelerate new treatments getting to clinical trial.

Professor Chinnery said: “ ̽��ֱ��new LifeArc centre unites scientific and clinical strengths from across the UK. For the first time we will form a single team, focussed on developing new treatments for mitochondrial diseases which currently have no cure.”

Adam Harraway has Mitochondrial Disease and says he lives in constant fear of what might go wrong next with his condition. “With rare diseases such as these, it can feel like the questions always outweigh the answers. ̽��ֱ��news of this investment from LifeArc fills me with hope for the future. To know that there are so many wonderful people and organisations working towards treatments and cures makes me feel seen and heard. It gives a voice to people who often have to suffer in silence, and I'm excited to see how this project can help Mito patients in the future."

LifeArc Centre for Rare Respiratory Diseases

Professor Stefan Marciniak will co-lead the LifeArc Centre for Rare Respiratory Diseases, a UK wide collaborative centre co-created in partnership with patients and charities. This Centre is a partnership between Universities and NHS Trusts across the UK, co-led by Edinburgh with Nottingham, Dundee, Cambridge, Southampton, ̽��ֱ�� College London and supported by six other centres (Belfast, Cardiff, Leeds, Leicester, Manchester and Royal Brompton).

For the first time ever, it will provide a single ‘go to’ centre that will connect children and adults with rare respiratory disease with clinical experts, researchers, investors and industry leaders across the UK. ̽��ֱ��£9.4M centre will create a UK-wide biobank of patient samples and models of disease that will allow researchers to advance pioneering therapies and engage with industry and regulatory partners to develop innovative human clinical studies.

Professor Marciniak said: “There are many rare lung diseases, and together those affected constitute a larger underserved group of patients. ̽��ֱ��National Translational Centre for Rare Respiratory Diseases brings together expertise from across the UK to find effective treatments and train the next generation of rare disease researchers.”

Former BBC News journalist and presenter, Philippa Thomas, has the rare incurable lung disease, Lymphangioleiomyomatosis (LAM). Her condition has stabilised but for many people, the disease can be severely life-limiting. Philippa said: “There is so little research funding for rare respiratory diseases, that getting treatment - let alone an accurate diagnosis - really does feel like a lottery. It is also terrifying being diagnosed with something your GP will never have heard of.”

Globally, there are more than 300 million people living with rare diseases. However, rare disease research can be fragmented. Researchers can lack access to specialist facilities, as well as advice on regulation, trial designs, preclinical regulatory requirements, and translational project management, which are vital in getting new innovations to patients.

Dr Catriona Crombie, Head of Rare Disease at LifeArc, says: “We’re extremely proud to be launching four new LifeArc Translational Centres for Rare Diseases. Each centre has been awarded funding because it holds real promise for delivering change for people living with rare diseases. These centres also have the potential to create a blueprint for accelerating improvements across other disease areas, including common diseases.”

Adapted from a press release from LifeArc

Cambridge researchers will play key roles in two new centres dedicated to developing improved tests, treatments and potentially cures for thousands of people living with rare medical conditions.

̽��ֱ��new LifeArc centre unites scientific and clinical strengths from across the UK

Patrick Chinnery

Alexander_Safonov (Getty)

Woman inhaling from a mask nebulizer

Yes

Cambridge researchers elected to Academy of Medical Sciences Fellowship 2023

lw355 — Thu, 18 May 2023 08:00:52 +0000

̽��ֱ��new Fellows have been elected to the Academy in recognition of their exceptional contributions to the advancement of biomedical and health science, cutting-edge research discoveries and translating developments into benefits for patients and wider society.

They join a prestigious Fellowship of 1,400 esteemed researchers who are central to the Academy’s work. This includes providing career support to the next generation of researchers and contributing to the Academy’s influential policy work to improve health in the UK and globally.

Professor Dame Anne Johnson PMedSci, President of the Academy of Medical Sciences, said: “These new Fellows are pioneering biomedical research and driving life-saving improvements in healthcare. It’s a pleasure to recognise and celebrate their exceptional talent by welcoming them to the Fellowship.

“This year, we are celebrating our 25th anniversary. ̽��ֱ��Fellowship is our greatest asset, and their broad expertise and dynamic ability has shaped the Academy to become the influential, expert voice of health. As we look to the future, the collective wisdom our new Fellows bring will be pivotal in achieving our mission to create an open and progressive research sector to improve the health of people everywhere.”

̽��ֱ��new Cambridge Fellows are:

Professor Charlotte Coles FMedSci

Professor of Breast Cancer Clinical Oncology, Department of Oncology, NIHR Research Professor and Director of Cancer Research UK RadNet Cambridge

Professor Coles leads practice-changing breast radiotherapy trials, has influenced international hypofractionation policy and is addressing global health, gender and equity challenges within the Lancet Breast Cancer Commission.

“It’s an honour to be elected as a new Fellow of the Academy of Medical Sciences. This is a result of research collaborations in Cambridge, the UK and internationally and I’d like to thank these wonderful colleagues, especially patient advocates,” said Coles.

“I hope to contribute to the Academy’s work to increase equity, diversity and inclusion within leadership roles, including lower- and middle-income countries, to enrich research and improve the culture in Medical Sciences.”

Professor Emanuele Di Angelantonio FMedSci

Professor of Clinical Epidemiology and Donor Health, Department of Public Health and Primary Care, and Head of Health Data Science Centre, Human Technopole (Milan)

Professor Di Angelantonio’s research has focused on addressing major clinical and public health priorities in cardiovascular disease (CVD) and transfusion medicine. His election recognises his many contributions both in helping resolve important controversies in CVD prevention strategies and in improving the safety and efficiency of blood donation.

“I am delighted and honoured to be elected to the Fellowship of the Academy of Medical Sciences, which I recognise is an outcome of the collaborations with many colleagues in UK and worldwide,” said Di Angelantonio.

“Research excellence across medical sciences and translation to health improvements has been at the centre of the Academy’s mission and I am very pleased to now be able to contribute to fulfilling this aim as a Fellow.”

Dr Rita Horvath FMedSci

Director of Research in Genetics of Rare Neurological Disorders in the Department of Clinical Neurosciences and Honorary Consultant in Neurology

Dr Horvath is an academic neurologist using genomics and biochemistry to diagnose rare, inherited neurological disorders, with a focus on mitochondrial diseases. Throughout her career she has combined fundamental experimental work with clinical studies. She pioneered the development and implementation of next generation sequencing in the diagnosis of rare neurogenetic diseases in the UK, leading to precision genetic approaches. She has established extensive international collaborations, having impact in Europe, but also for underserved groups in countries where such expertise is lacking.

“I am delighted and honoured to be elected to this Fellowship, which recognises the impact of my work. I would not have achieved it without the support of my excellent colleagues and research team, for which I give my sincere thanks,” said Horvath.

“As a Hungarian woman working in different countries before I arrived in the UK in 2007, I feel particularly proud of this award, which I recognise is an outcome of the open and fair research environment in Cambridge. This Fellowship enables me to further expand my research to develop effective treatments for patients with rare inherited neurological diseases.”

Professor Eric Miska FMedSci

Herchel Smith Chair of Molecular Genetics and Head of Department of Biochemistry, Affiliated Senior Group Leader at the Gurdon Institute, Associate Faculty at the Wellcome Sanger Institute and Fellow of St John’s College

Professor Miska is a molecular geneticist who has carried out pioneering work on RNA biology. His work led to fundamentally new insights into how small RNA molecules control our genes and protect organisms from selfish genes and viruses, and how RNA can carry heritable information across generations. Miska is Founder and Director of STORM Therapeutics Ltd, which creates novel therapies that inhibit RNA modifying enzymes for use in oncology and other diseases.

“Wonderful recognition of the work of an amazing team of researchers I have the pleasure to work with,” said Miska. “Most of our research has been done using the roundworm C. elegans. As Friedrich Nietzsche wrote in Thus Spoke Zarathustra: ‘You have evolved from worm to man, but much within you is still worm’.”

Professor Serena Nik-Zainal FMedSci

NIHR Research Professor, Professor of Genomic Medicine and Bioinformatics, Department of Medical Genetics and Early Cancer Institute, and Honorary Fellow of Murray Edwards College

Professor Nik-Zainal’s research is focused on investigating the vast number of mutations that occur in human DNA from birth, causing patterns called ‘mutational signatures’, and the associated physiological changes to cellular function, in progressive diseases such as cancer and neurodegeneration. She uses a combination of experimental and computational methods to understand biology and to develop clinical tests for early detection and precision diagnostics. Her team also builds computational tools to enable genomic advances become more accessible across the NHS.

“What an honour it is to be elected to the Fellowship. This is a wonderful recognition of the work from my team,” said Nik-Zainal. “We are thrilled and hugely indebted to all our inspiring collaborators, supporters and patients, who have shared in our passion and joined us on our path, exploring biomedical science and translating insights into patient benefit.”

Professor Julian Rayner FMedSci

Director of the Cambridge Institute for Medical Research, School of Clinical Medicine, Honorary Faculty at the Wellcome Sanger Institute, and Director of Wellcome Connecting Science

Professor Rayner’s research has made significant contributions to our understanding of how malaria parasites recognise and invade human red blood cells to cause disease. His work has helped to identify new vaccine targets, such as a protein essential for red blood cell invasion that is now in early stage human vaccine testing, and inform antimalarial drug development, through co-leading the first ever genome-scale functional screens in malaria parasites. He collaborates closely with researchers in malaria-endemic countries and is strongly committed to engaging public audiences with the process and outcomes of science.

“Malaria is a devastating and too often forgotten disease that still kills more than half a million children every year. Tackling it requires deep collaboration and working across disciplines. I’m enormously honoured by this announcement, which reflects not my work but the work of all the talented people I’ve been lucky enough to host in my lab, and collaborations with friends and colleagues across the world,” said Rayner.

“I’m excited to become a Fellow of the Academy of Medical Sciences because I strongly share their conviction that science is not just for scientists. I believe that dialogue, learning and public engagement are all fundamental and essential parts of the research process, and I look forward to contributing to their leading role in these areas.”

Professor James Rowe FMedSci

Professor of Cognitive Neurology, Department of Clinical Neurosciences, and MRC Cognition and Brain Sciences Unit

Professor Rowe leads a highly interdisciplinary research team at the Cambridge Centre for Frontotemporal Dementia and at Dementias Platform UK to improve the diagnosis and treatment of people affected by dementia. His work integrates cognitive neuroscience, brain imaging, fluidic biomarkers, computational models and neuropathology for experimental medicine studies and clinical trials. He is motivated by his busy clinical practice and the need for better diversity and inclusivity throughout medical research.

“I am delighted and honoured to be elected to the Fellowship of the Academy of Medical Sciences. It is a testament to the many wonderful colleagues and students I have been fortunate to work with, and to inspirational mentors,” said Rowe.

“Research excellence, and translation of research for direct human benefit, comes from innovation and collaboration in diverse cross-disciplinary teams. I believe in the vision and values of the Academy as the route to better health for all.”

In addition, two researchers from the wider community have also been elected:

Dr Trevor Lawley FMedSci, Senior Group Leader, Wellcome Sanger Institute and Chief Scientific Officer, Microbiotica

Professor Ben Lehner FRS FMedSci, Senior Group Leader, Human Genetics Programme, Wellcome Sanger Institute

Seven Cambridge ̽��ֱ�� researchers are among the 59 biomedical and health researchers elected to the Academy of Medical Sciences Fellowship.

As we look to the future, the collective wisdom our new Fellows bring will be pivotal in achieving our mission to create an open and progressive research sector to improve the health of people everywhere

Professor Dame Anne Johnson, President of the Academy of Medical Sciences

Clockwise from top left: E. Di Angelantonio, J. Rayner, J. Rowe, R. Horvath, S. Nik-Zainal, E. Miska, C. Coles

̽��ֱ��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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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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Licence type:

Attribution

Darwin Lectures

ps748 — Wed, 18 Jan 2023 13:57:06 +0000

Isolation is the theme of the 2023 Lecture Series

Cambridge researchers join new £2 million UK consortium to tackle monkeypox outbreak

cjb250 — Wed, 19 Oct 2022 23:01:27 +0000

̽��ֱ��consortium has received £2 million from the Biotechnology and Biosciences Research Council and the Medical Research Council, both part of UK Research and Innovation (UKRI). It is led by the Pirbright Institute and the MRC- ̽��ֱ�� of Glasgow Centre for Virus Research.

Researchers will work closely with experts at government agencies – the Animal and Plant Health Agency, UK Health Security Agency, and Defence Science and Technology Laboratory – to study the current outbreak and inform the public health response in the UK and internationally.

Cambridge scientists Professor Geoffrey Smith from the Department of Pathology and Professor Mike Weekes from the Cambridge Institute for Medical Research and Department of Medicine are among the key scientists involved in the consortium.

Professor Weekes said: "Monkeypox has become a really important global pathogen, reaching more than 50 countries worldwide in a matter of months. Although we have an effective vaccine and treatment, global roll-out has so far proved challenging, emphasising the importance of a comprehensive understanding of this virus. ̽��ֱ��UK consortium includes researchers from multiple different disciplines, and I anticipate the data we generate will rapidly help understand how the virus can be targeted in new ways to prevent disease."

Professor Smith said: “Few would have predicted that monkeypox virus would be causing a global epidemic in 2022. ̽��ֱ��ability to respond quickly to this new challenge has been helped greatly not just by the swift and welcome response of UKRI, but also by decades of support for the study of orthopoxviruses from UKRI and the Wellcome Trust. ̽��ֱ��information gained from those studies is valuable in the fight against monkeypox virus.”

̽��ֱ��monkeypox virus outbreak originated in West Africa. ̽��ֱ��current worldwide outbreak of cases spreading outside this area was first identified in May 2022. This is the first time that many monkeypox cases and clusters have been reported in non-endemic areas.

In the UK there have been more than 3,400 confirmed cases since May, although case numbers are currently falling. Internationally, WHO reports it has spread to 106 countries and territories with 25 confirmed deaths.

Professor Melanie Welham, Executive Chair of BBSRC, said: “One of the real strengths of the UK’s scientific response to disease outbreaks is the way that we can draw on leading researchers from all over the country, who can pool their expertise to deliver results, fast. Long-term support for animal and human virus research has ensured we have the capability to respond with agility.

“This new national consortium will study the unprecedented monkeypox outbreak to better understand how to tackle it. This will feed rapidly into global public health strategies, developing new diagnostic tests and identifying potential therapies.”

̽��ֱ��consortium will focus on building our understanding in a number of key areas, including:

Developing new tests and identifying potential control measures:

Developing sensitive point-of-care tests to speed up diagnosis, such as lateral flow tests or LAMP* tests. ̽��ֱ��lateral flow test development will be conducted with Global Access Diagnostics (GADx) to develop a product which could later be manufactured at scale and used clinically worldwide, including in low/middle income countries.
Screening potential drugs to treat monkeypox in human cells in the lab to determine which ones could be developed for further testing.
Studying the virus, how it infects humans and its susceptibility to the immune response to identify targets for future therapies.

Studying the virus:

Characterising the genome of the virus and studying how it is evolving, and how this is linked to changes in the transmission and pathology of the virus.
Understanding the human immune response to the virus and the vaccine, including studying samples from infected individuals.
Identifying animal reservoirs and potential spill-over routes of transmission between animals and humans.

Learning from the vaccine roll-out:

Studying the effectiveness of the smallpox vaccine by tracking the immune responses after primary and secondary vaccination of up to 200 individuals.

Professor Bryan Charleston, co-lead from ̽��ֱ��Pirbright Institute, said: “ ̽��ֱ��implications of the current monkeypox outbreak are huge. As well as tackling the current outbreak, we also need to be fully prepared for next outbreak, because worldwide there’s a huge reservoir of infection. One of the key ways we can do this is to develop rapid tests, which are very important to help clinicians on the front line to manage the disease.”

Professor Massimo Palmarini, co-lead from the MRC- ̽��ֱ�� of Glasgow Centre for Virus Research, said: “Monkeypox is public health challenge, so taking decisive, collective action to better understand this virus is paramount. By bringing together research expertise in different areas, we will harness the UK’s world-leading knowledge to learn more about how the virus works and spreads and provide the foundations for the development of potential new treatments.”

Adapted from a press release from UKRI

Cambridge is among 12 institutions across the UK that will be working together to tackle the monkeypox outbreak, developing better diagnostic tests, identifying potential therapies and studying vaccine effectiveness and the virus’ spread.

Few would have predicted that monkeypox virus would be causing a global epidemic in 2022

Geoffrey Smith

BlackJack3D

Monkeypox virus - 3D render

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New route to evolution: how DNA from our mitochondria gets into our genomes

cjb250 — Wed, 05 Oct 2022 15:00:50 +0000

In a study published today in Nature, researchers at the ̽��ֱ�� of Cambridge and Queen Mary ̽��ֱ�� of London show that mitochondrial DNA also appears in some cancer DNA, suggesting that it acts as a sticking plaster to try and repair damage to our genetic code.

Mitochondria are tiny ‘organelles’ that sit within our cells, where they act like batteries, providing energy in the form of the molecule ATP to power the cells. Each mitochondrion has its own DNA – mitochondrial DNA – that is distinct to the rest of the human genome, which is comprised of nuclear DNA.

Mitochondrial DNA is passed down the maternal line – that is, we inherit it from our mothers, not our fathers. However, a study published in PNAS in 2018 from researchers at the Cincinnati Children’s Hospital Medical Center in the USA reported evidence that suggested some mitochondrial DNA had been passed down the paternal line.

To investigate these claims, the Cambridge team looked at the DNA from over 11,000 families recruited to Genomics England’s 100,000 Genomes Project, searching for patterns that looked like paternal inheritance. ̽��ֱ��Cambridge team found mitochondrial DNA ‘inserts’ in the nuclear DNA of some children that were not present in that of their parents. This meant that the US team had probably reached the wrong conclusions: what they had observed were not paternally-inherited mitochondrial DNA, but rather these inserts.

Now, extending this work to over 66,000 people, the team showed that the new inserts are actually happening all the time, showing a new way our genome evolves.

Professor Patrick Chinnery, from the Medical Research Council Mitochondrial Biology Unit and Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, explained: “Billions of years ago, a primitive animal cell took in a bacterium that became what we now call mitochondria. These supply energy to the cell to allow it to function normally, while removing oxygen, which is toxic at high levels. Over time, bits of these primitive mitochondria have passed into the cell nucleus, allowing their genomes to talk to each other.

“This was all thought to have happened a very long time ago, mostly before we had even formed as a species, but what we've discovered is that that’s not true. We can see this happening right now, with bits of our mitochondrial genetic code transferring into the nuclear genome in a measurable way.”

̽��ֱ��team estimate that mitochondrial DNA transfers to nuclear DNA in around one in every 4,000 births. If that individual has children of their own, they will pass these inserts on – the team found that most of us carry five of the new inserts, and one in seven of us (14%) carry very recent ones. Once in place, the inserts can occasionally lead to very rare diseases, including a rare genetic form of cancer.

It isn’t clear exactly how the mitochondrial DNA inserts itself – whether it does so directly or via an intermediary, such as RNA – but Professor Chinnery says it is likely to occur within the mother’s egg cells.

When the team looked at sequences taken from 12,500 tumour samples, they found that mitochondrial DNA was even more common in tumour DNA, arising in around one in 1,000 cancers, and in some cases, the mitochondrial DNA inserts actually causes the cancer.

“Our nuclear genetic code is breaking and being repaired all the time,” said Professor Chinnery. “Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours.”

More than half (58%) of the insertions were in regions of the genome that code for proteins. In the majority of cases, the body recognises the invading mitochondrial DNA and silences it in a process known as methylation, whereby a molecule attaches itself to the insert and switches it off. A similar process occurs when viruses manage to insert themselves into our DNA. However, this method of silencing is not perfect, as some of the mitochondrial DNA inserts go on to be copied and move around the nucleus itself.

̽��ֱ��team looked for evidence that the reverse might happen – that mitochondrial DNA absorbs parts of our nuclear DNA – but found none. There are likely to be several reasons why this should be the case.

Firstly, cells only have two copies of nuclear DNA, but thousands of copies of mitochondrial DNA, so the chances of mitochondrial DNA being broken and passing into the nucleus are much greater than the other way around.

Secondly, the DNA in mitochondria is packaged inside two membranes and there are no holes in the membrane, so it would be difficult for nuclear DNA to get in. By contrast, if mitochondrial DNA manages to get out, holes in the membrane surrounding nuclear DNA would allow it pass through with relative ease.

Professor Sir Mark Caulfield, Vice Principal for Health at Queen Mary ̽��ֱ�� of London, said: “I am so delighted that the 100,000 Genomes Project has unlocked the dynamic interplay between mitochondrial DNA and our genome in the cell’s nucleus. This defines a new role in DNA repair, but also one that could occasionally trigger rare disease, or even malignancy.”

̽��ֱ��research was mainly funded by the Medical Research Council, Wellcome, and the National Institute for Health Research.

Reference
Wei, E et al. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature; 5 Oct 2022; DOI: 10.1038/s41586-022-05288-7

Scientists have shown that in one in every 4,000 births, some of the genetic code from our mitochondria – the ‘batteries’ that power our cells – inserts itself into our DNA, revealing a surprising new insight into how humans evolve.

Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours

Patrick Chinnery

Dr David Furness

Mitochondria surrounded by cytoplasm

Yes

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