̽��ֱ�� of Cambridge - Gabriel Balmus

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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Lab-grown ‘mini brains’ hint at treatments for neurodegenerative diseases

cjb250 — Thu, 21 Oct 2021 15:00:41 +0000

A common form of motor neurone disease, amyotrophic lateral sclerosis, often overlaps with frontotemporal dementia (ALS/FTD) and can affect younger people, occurring mostly after the age of 40-45. These conditions cause devastating symptoms of muscle weakness with changes in memory, behaviour and personality. Being able to grow small organ-like models (organoids) of the brain allows the researchers to understand what happens at the earliest stages of ALS/FTD, long before symptoms begin to emerge, and to screen for potential drugs.

In general, organoids, often referred to as ‘mini organs’, are being used increasingly to model human biology and disease. At the ̽��ֱ�� of Cambridge alone, researchers use them to repair damaged livers, study SARS-CoV-2 infection of the lungs and model the early stages of pregnancy, among many other areas of research.

Typically, researchers take cells from a patient’s skin and reprogramme the cells back to their stem cell stage – a very early stage of development at which they have the potential to develop into most types of cell. These can then be grown in culture as 3D clusters that mimic particular elements of an organ. As many diseases are caused in part by defects in our DNA, this technique allows researchers to see how cellular changes – often associated with these genetic mutations – lead to disease.

Scientists at the John van Geest Centre for Brain Repair, ̽��ֱ�� of Cambridge, used stem cells derived from patients suffering from ALS/FTD to grow brain organoids that are roughly the size of a pea. These resemble parts of the human cerebral cortex in terms of their embryonic and fetal developmental milestones, 3D architecture, cell-type diversity and cell-cell interactions.

Although this is not the first time scientists have grown mini brains from patients with neurodegenerative diseases, most efforts have only been able to grow them for a relatively short time frame, representing a limited spectrum of dementia-related disorders. In findings published today in Nature Neuroscience, the Cambridge team reports growing these models for 240 days from stem cells harbouring the commonest genetic mutation in ALS/FTD, which was not previously possible – and in unpublished work the team has grown them for 340 days.

Dr András Lakatos, the senior author who led the research in Cambridge’s Department of Clinical Neurosciences, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

While organoids are usually grown as balls of cells, first author Dr Kornélia Szebényi generated patient cell-derived organoid slice cultures in Dr Lakatos’ laboratory. This technique ensured that most cells within the model could receive the nutrients required to keep them alive.

Dr Szebényi said: “When the cells are clustered in larger spheres, those cells at the core may not receive sufficient nutrition, which may explain why previous attempts to grow organoids long term from patients’ cells have been difficult.”

Using this approach, Dr Szebényi and colleagues observed changes occurring in the cells of the organoids at a very early stage, including cell stress, damage to DNA and changes in how the DNA is transcribed into proteins. These changes affected those nerve cells and other brain cells known as astroglia, which orchestrate muscle movements and mental abilities.

“Although these initial disturbances were subtle, we were surprised at just how early changes occurred in our human model of ALS/FTD,” added Dr Lakatos. “This and other recent studies suggest that the damage may begin to accrue as soon as we are born. We will need more research to understand if this is in fact the case, or whether this process is brought forward in organoids by the artificial conditions in the dish.”

As well as being useful for understanding disease development, organoids can be a powerful tool for screening potential drugs to see which can prevent or slow disease progression. This is a crucial advantage of organoids, as animal models often do not show the typical disease-relevant changes, and sampling the human brain for this research would be unfeasible.

̽��ֱ��team showed that a drug, GSK2606414, was effective at relieving common cellular problems in ALS/FTD, including the accumulation of toxic proteins, cell stress and the loss of nerve cells, hence blocking one of the pathways that contributes to disease. Similar drugs that are more suitable as medications and approved for human use are now being tested in clinical trials for neurodegenerative diseases.

Dr Gabriel Balmus from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, collaborating senior author, said: “By modelling some of the mechanisms that lead to DNA damage in nerve cells and showing how these can lead to various cell dysfunctions, we may also be able to identify further potential drug targets.”

Dr Lakatos added: “We currently have no very effective options for treating ALS/FTD, and while there is much more work to be done following our discovery, it at least offers hope that it may in time be possible to prevent or to slow down the disease process.

“It may also be possible in future to be able to take skin cells from a patient, reprogramme them to grow their ‘mini brain’ and test which unique combination of drugs best suits their disease.”

̽��ֱ��study was primarily funded by the Medical Research Council UK, Wellcome Trust and the Evelyn Trust.

Reference

Szebényi, K et al. Human ALS/FTD Brain Organoid Slice Cultures Display Distinct Early Astrocyte and Targetable Neuronal Pathology. Nature Neuroscience; 21 Oct 2021; DOI: 10.1038/s41593-021-00923-4

Cambridge researchers have developed ‘mini brains’ that allow them to study a fatal and untreatable neurological disorder causing paralysis and dementia – and for the first time have been able to grow these for almost a year.

Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell

András Lakatos

Andras Lakatos

Mini brain organoids showing cortical-like structures

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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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