̽��ֱ�� of Cambridge - CHDI Foundation

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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Sheep are able to recognise human faces from photographs

cjb250 — Wed, 08 Nov 2017 01:16:01 +0000

̽��ֱ��study, published today in the journal Royal Society: Open Science, is part of a series of tests given to the sheep to monitor their cognitive abilities. Because of the relatively large size of their brains and their longevity, sheep are a good animal model for studying neurodegenerative disorders such as Huntington’s disease.

̽��ֱ��ability to recognise faces is one of the most important human social skills. We recognise familiar faces easily, and can identify unfamiliar faces from repeatedly presented images. As with some other animals such as dogs and monkeys, sheep are social animals that can recognise other sheep as well as familiar humans. Little is known, however, about their overall ability to process faces.

Researchers from Cambridge’s Department of Physiology, Development and Neuroscience trained eight sheep to recognise the faces of four celebrities (Fiona Bruce, Jake Gyllenhaal, Barack Obama and Emma Watson) from photographic portraits displayed on computer screens.

Training involved the sheep making decisions as they moved around a specially-designed pen. At one end of the pen, they would see two photographs displayed on two computer screens and would receive a reward of food for choosing the photograph of the celebrity (by breaking an infrared beam near the screen); if they chose the wrong photograph, a buzzer would sound and they would receive no reward. Over time, they learned to associate a reward with the celebrity’s photograph.

After training, the sheep were shown two photographs – the celebrity’s face and another face. In this test, sheep correctly chose the learned celebrity face eight times out of ten.

In these initial tests, the sheep were shown the faces from the front, but to test how well they recognised the faces, the researchers next showed them the faces at an angle. As expected, the sheep’s performance dropped, but only by about 15% - a figure comparable to that seen when humans perform the task.

Finally, the researchers looked at whether sheep were able to recognise a handler from a photograph without pre-training. ̽��ֱ��handlers typically spend two hours a day with the sheep and so the sheep are very familiar with them. When a portrait photograph of the handler was interspersed randomly in place of the celebrity, the sheep chose the handler’s photograph over the unfamiliar face seven out of ten times.

During this final task the researchers observed an interesting behaviour. Upon seeing a photographic image of the handler for the first time – in other words, the sheep had never seen an image of this person before – the sheep did a 'double take'. ̽��ֱ��sheep checked first the (unfamiliar) face, then the handler’s image, and then the unfamiliar face again before making a decision to choose the familiar face, of the handler.

“Anyone who has spent time working with sheep will know that they are intelligent, individual animals who are able to recognise their handlers,” says Professor Jenny Morton, who led the study. “We’ve shown with our study that sheep have advanced face-recognition abilities, comparable with those of humans and monkeys.

“Sheep are long-lived and have brains that are similar in size and complexity to those of some monkeys. That means they can be useful models to help us understand disorders of the brain, such as Huntington’s disease, that develop over a long time and affect cognitive abilities. Our study gives us another way to monitor how these abilities change, particularly in sheep who carry the gene mutation that causes Huntington’s disease.”

Professor Morton’s team recently began studying sheep that have been genetically modified to carry the mutation that causes Huntington’s disease.

Huntington’s disease affects more than 6,700 people in the UK. It is an incurable neurodegenerative disease that typically begins in adulthood. Initially, the disease affects motor coordination, mood, personality and memory, as well as other complex symptoms including impairments in recognising facial emotion. Eventually, patients have difficulty in speech and swallowing, loss of motor function and die at a relatively early age. There is no known cure for the disease, only ways to manage the symptoms.

̽��ֱ��research was supported by the CHDI Foundation, Inc., a US-based charitable trust that supports biomedical research related to Huntington’s disease.

Reference
Knolle, F et al. Sheep recognize familiar and unfamiliar human faces from two-dimensional images. Royal Society Open Science; 8 Nov 2017; DOI: 10.1098/rsos.171228

Sheep can be trained to recognise human faces from photographic portraits – and can even identify the picture of their handler without prior training – according to new research from scientists at the ̽��ֱ�� of Cambridge.

We’ve shown that sheep have advanced face-recognition abilities, comparable with those of humans and monkeys

Jenny Morton

Sheep can recognise human faces from photographs

Jenny Morton

Sheep correctly identifying face

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

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New study identifies possible early warning signs of Huntington’s disease

cjb250 — Thu, 23 Feb 2017 11:15:23 +0000

Researchers from the ̽��ֱ�� of Cambridge and ̽��ֱ�� of Surrey have identified early biomarkers of disease during examinations of Huntington’s disease sheep still at a pre-symptomatic stage of the disease.

Up until this point, the five-year-old sheep had displayed no signs of the illness, but the comprehensive study identified clear metabolic changes in the animals carrying the genetic variant. These new findings reveal that Huntington’s disease affects important metabolic processes in the body prior to the appearance of physical symptoms.

Huntington’s disease affects more than 6,700 people in the UK. It is an incurable neurodegenerative disease: patients typically die 10-25 years after diagnosis.

̽��ֱ��disease is caused by a mutation in the huntingtin gene. Genetic information is coded in DNA that is made up of a repeated string of four molecules known as nucleotides, or bases – A, C, G and T. Changes in the genetic code of the huntingtin gene leads directly to disease. ̽��ֱ��gene contains a repeated string of CAG bases: in healthy individuals, the CAG repeat is around 20 CAGs long, but if the repeat has 36 or more CAGs, an individual will develop Huntington’s disease. ̽��ֱ��sheep model of Huntington’s disease, which carries a CAG repeat in the disease-causing range, has been developed to increase knowledge about the condition.

During this study, researchers took blood samples from the normal and Huntington’s disease animals every two hours over a 24-hour period and assessed their metabolic profiles using a targeted metabolomics approach established at the ̽��ֱ�� of Surrey. Unlike previous research in this area, which was affected by to external environmental factors that impacted upon metabolic profiling, sheep in this study were monitored in a well-controlled setting, negating any outside influences.

Blood measurements found startling differences in the biochemistry of the sheep carrying the disease-causing variant, compared to the normal sheep. Significant changes were observed in 89 of the 130 metabolites measured in their blood, with increased levels of the amino acids, arginine and citrulline, and decreases in sphingolipids and fatty acids that are commonly found in brain and nervous tissue.

̽��ֱ��alterations in these metabolites, which include key components of the urea cycle and nitric oxide pathways (both vital body processes), suggest that both of these processes are dysregulated in the early stages of Huntington’s disease, and that the illness affects the body long before physical symptoms appear.

̽��ֱ��identification of these biomarkers may help to track disease in pre-symptomatic patients, and could help researchers develop strategies to remedy the biochemical abnormalities.

Professor Debra Skene from the ̽��ֱ�� of Surrey said: “Metabolic profiling has revealed novel biomarkers that will be useful to monitor Huntington’s disease progression.

“Our research shows that this disease affects the body in a number of ways before the tell-tale signs of Huntington’s disease become visible.”

Professor Jenny Morton from the ̽��ֱ�� of Cambridge said: “Despite its devastating impacts on patients and their families, there are currently limited treatments options, and no cure for Huntington’s disease. ̽��ֱ��development of objective and reliable biomarkers that can be rapidly measured from blood samples becomes immeasurably important once clinical trials for therapies begin.

“ ̽��ֱ��more we learn about this devastating illness the better chance we have of finding a cure.”

̽��ֱ��research was funded by the CHDI Foundation and the Biotechnology and Biological Sciences Research Council.

Reference
Skene, DJ et al. Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers. Scientific Reports; 22 Feb 2017; DOI: 10.1038/srep43030

Adapted from a press release by the ̽��ֱ�� of Surrey.

Early warning signs of Huntington’s disease have been uncovered in a sheep carrying the human disease-causing genetic variant, providing new insights into this devastating illness, a new study in Scientific Reports has found.

Despite its devastating impacts on patients and their families, there are currently limited treatments options, and no cure for Huntington’s disease

Jenny Morton

Marco Marcegaglia

Sheep

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

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