探花直播 of Cambridge - Peter St George-Hyslop

Mechanism behind neuron death in motor neurone disease and frontotemporal dementia discovered

cjb250 — Fri, 20 Apr 2018 13:14:58 +0000

Writing in聽Cell, the researchers from the 探花直播 of Cambridge and 探花直播 of Toronto also identify potential therapeutic targets for these currently incurable diseases.

ALS is a progressive and terminal disease that damages the function of nerves and muscle, affecting up to 5,000 adults in the UK at any one time. Frontotemporal dementia is a form of dementia that causes changes in personality and behaviour, and language difficulties.

A common characteristic of ALS and frontotemporal dementia is the build-up of clumps of misfolded RNA-binding proteins, including a protein called FUS, in the brain and spinal cord. 聽This leads to the death of neurons, which stops them from communicating with each other and from reaching the muscles.

FUS proteins can change back and forth from small liquid droplets (resembling oil droplets in water) to small gels (like jelly) inside nerve cells. As the FUS protein condenses (from droplets to gel) it captures RNA and transfers it to remote parts of the neuron that are involved in making connections (known as synapses) with other neurons. Here, the protein 鈥榤elts鈥� and releases the RNA. 探花直播RNA are then used to create new proteins in the synapses, which are essential for keeping the synapses working properly, especially during memory formation and learning. 聽

In frontotemporal dementia and ALS, the proteins become permanently stuck as abnormally dense gels, trapping the RNA and making it unavailable for use. This damages nerve cells by blocking their ability to make the proteins needed for synaptic function and leads to the death of neurons in the brain and spinal cord.

In research funded by Wellcome, scientists used human cells that resembled neurons and neurons from frogs to investigate how the change in FUS from liquid droplets to small gels process is regulated and what makes it go awry. They found that this reversible process was tightly controlled by enzymes which chemically alter FUS making it able or unable to form droplets and gels. In frontotemporal dementia, the abnormal gelling was found to be caused by defects in the chemical modification of FUS. In motor neuron disease, it was caused by mutations in the FUS protein itself which meant it was no longer able to change form.

This research provides new ideas and tools to find ways to prevent or reverse the abnormal gelling of FUS as a treatment for these devastating diseases. Potential therapeutic targets identified by the researchers are the enzymes that regulate the chemical modification of FUS and the molecular chaperones that facilitate FUS proteins to change its form. These treatments would need to allow FUS to continue moving between safe reversible states (liquid droplets and reversible gels) but prevent FUS from dropping into the dense, irreversible gel states that cause disease.

Professor Peter St George-Hyslop from the Cambridge Institute for Medical Research said: 鈥淭his was a very exciting set of experiments where we were able to apply聽cutting edge tools from physics, chemistry and neurobiology to understand how the FUS protein normally works in nerve cells, and how it goes wrong in motor neurone disease and dementia. It now opens up a new avenue of work to use this knowledge to identify ways to prevent the abnormal gelling of FUS in motor neurone disease and dementia.鈥�

Dr Giovanna Lalli, from Wellcome鈥檚 Neuroscience and Mental Health team, said: 鈥淢otor neurone disease and frontotemporal dementia are devastating diseases that affect thousands of people across the UK, resulting in severe damage to the brain and spinal cord. By bringing together an interdisciplinary team of researchers, this study provides important new insights into a fundamental process underlying neurodegeneration. Through their research, the team have uncovered promising new ways to tackle these diseases.鈥�

Reference
Qamar, S et al. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-蟺 Interactions. Cell; 19 Apr 2018; DOI: 10.1016/j.cell.2018.03.056

Adapted from a press release by Wellcome

Scientists have identified the molecular mechanism that leads to the death of neurons in聽amyotrophic聽lateral sclerosis (also known as ALS or motor neurone disease) and a common form of聽frontotemporal聽dementia.

This was a very exciting set of experiments where we were able to apply cutting edge tools from physics, chemistry and neurobiology to understand how the FUS protein normally works in nerve cells, and how it goes wrong in motor neurone disease and dementia

Peter St George-Hyslop

ColiN00B

Nerve cells

探花直播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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Breaking the mould: Untangling the jelly-like properties of diseased proteins

cjb250 — Thu, 29 Oct 2015 16:30:11 +0000

A common characteristic of neurodegenerative diseases 鈥� such as Alzheimer鈥檚, Parkinson鈥檚 and Huntington鈥檚 disease 鈥� is the build-up of 鈥榤isfolded鈥� proteins, which cause irreversible damage to the brain. For example, Alzheimer鈥檚 disease sees the build-up of beta-amyloid 鈥榩laques鈥� and tau 鈥榯angles鈥�.

In the case of some forms of motor neurone disease (also known as amyotrophic lateral sclerosis, or ALS) and frontotemporal dementia, it is the build up of 鈥榓ssemblies鈥� of misshapen FUS protein and several other RNA-binding proteins that is associated with disease. However, the assembly of these RNA binding proteins has several differences to conventional protein aggregates seen in Alzheimer鈥檚 disease and Parkinson鈥檚 disease and as a result, the significance of the build-up of these proteins and how it occurs has until now been unclear.

FUS is an RNA-binding protein, which has a number of important functions in regulating RNA transcription (the first step in DNA expression) and splicing in the nucleus of cells. FUS also has functions in the cytoplasm of cells involved in regulating the translation of RNA into proteins. There are several other similar RNA binding proteins: a common feature of all of them is that in addition to having domains to bind RNA they also have domains where the protein appears to be unfolded or unstructured.

In a study published today in the journal Neuron, scientists at the 探花直播 of Cambridge examined FUS鈥檚 physical properties to demonstrate how the protein鈥檚 unfolded domain enables it to undergo reversible 鈥榩hase transitions鈥�. In other words, it can change back and forth from a fully soluble 鈥榤onomer鈥� form into distinct localised accumulations that resemble liquid droplets and then further condense into jelly-like structures that are known as hydrogels. During these changes, the protein 鈥榓ssemblies鈥� capture and release RNA and other proteins. In essence this process allows cellular machinery for RNA transcription and translation to be condensed in high concentrations within restricted three-dimensional space without requiring a limiting membrane, thereby helping to easily regulate these vital cellular processes.

Using the nematode worm C. elegans as a model of ALS and frontotemporal dementia, the team was then able to also show that this process can become irreversible. Mutated FUS proteins cause the condensation process to go too far, forming thick gels that are unable to return to their soluble state. As a result, these irreversible gel-like assemblies trap other important proteins, preventing them carrying out their usual functions. One consequence is that it affects the synthesis of new proteins in nerve cell axons (the trunk of a nerve cell).

Importantly, the researchers also showed that by disrupting the formation of these irreversible assemblies (for example, by targeting with particular small molecules), it is possible to rescue the impaired motility and prolong the worm鈥檚 lifespan.

Like jelly on a plate

探花直播behaviour of FUS can be likened to that of a jelly, explains Professor Peter St George Hyslop from the Cambridge Institute for Medical Research.

When first made, jelly is runny, like a liquid. As it cools the fridge, it begins to set, initially becoming slightly thicker than water, but still runny as the gelatin molecules forms into longer, fibre-like chains known as fibrils. If you dropped a droplet of this nearly-set jelly into water, it would (at least briefly) remain distinct from the surrounding water 鈥� a 鈥榣iquid droplet鈥� within a liquid.

As the jelly cools further in the fridge, the gelatin fibres condense more, and it eventually becomes a firmly set jelly that can be flipped out of the mould onto a plate. This set jelly is a 鈥榟ydrogel鈥�, a loose meshwork of protein (gelatin) fibrils that is dense enough to hold the water inside the spaces between its fibres. 探花直播set jelly holds the water in a constrained 3D space 鈥� and depending on the recipe, there may be some other 鈥榗argo鈥� suspended within the jelly, such as bits of fruit (in the case of FUS this 鈥榗argo鈥� might be ribosomes, other proteins, enzymes or RNA, for example).

When the jelly is stored in a cool room, the fruit is retained in the jelly. This means the fruit (or ribosomes, etc) can be moved around the house and eventually put on the dinner table (or in the case of FUS, be transported to parts of a cell with unique protein synthesis requirements).

If the jelly is re-warmed, it melts and releases its fruit, which then float off鈥�. But if the liquid molten jelly is put back in the fridge and re-cooled, it re-makes a firm hydrogel again, and the fruit is once again trapped. In theory, this cycle of gel-melt-gel-melt can be repeated endlessly.

However, if the jelly is left out, the water will slowly evaporate, and the jelly condenses down, changing from a soft, easily-melted jelly to a thick, rubbery jelly. 聽(In fact, jelly is often sold as a dense cube like this.) In this condensed jelly, the meshwork of protein fibrils are much closer together and it becomes increasingly difficult to get the condensed jelly to melt (you would have to pour boiling water on it to get it to melt). Because the condensed jelly is not easily meltable when it gets to this state, any cargo (fruit, ribosomes, etc.) within the jelly essentially becomes irreversibly trapped.

In the case of FUS and other RNA binding proteins, the 鈥榟ealthy鈥� proteins only very rarely spontaneously over-condense. However, disease-causing mutations make these proteins much more prone to spontaneously 鈥巆ondense down into thick fibrous gels, trapping their cargo (in this case the ribosomes, etc), which then become unavailable for use.

So essentially, this new research shows that the ability of some proteins to self-assemble into聽liquid droplets and (slightly more viscous) jellies/hydrogel is a useful property that allows cells to transiently concentrate cellular machinery into a constrained 3D space in order to perform key tasks, and then disassemble and disperse the machinery when not needed. It is probably faster and less energy-costly than doing the same thing inside intracellular membrane-bound vesicles 鈥� but that same property can go too far, leading to disease.

Professor St George Hyslop says: 鈥淲e鈥檝e shown that a particular group of proteins can regulate vital cellular processes by their distinct ability to transition between different states. But this essential property also makes them vulnerable to forming more fixed structures if mutated, disrupting their normal function and causing disease.

鈥� 探花直播same principles are likely to be at play in other more common forms of these diseases due to mutation in other related binding proteins. Understanding what is in these assemblies should provide further targets for disease treatments.

鈥淥ur approach shows the importance of considering the mechanisms of diseases as not just biological, but also physical processes. By bringing together people from the biological and physical sciences, we鈥檝e been able to better understand how misshapen proteins build up and cause disease.鈥�

探花直播research was funded by in the UK by the Wellcome Trust, Medical Research Council and National Institutes of Health Research, in Canada by Canadian Institutes of Health Research, and in the US by National Institutes of Health.

Reference
Murakami, T et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron; 29 Oct 2015

Scientists at the 探花直播 of Cambridge have identified a new property of essential proteins which, when it malfunctions, can cause the build up, or 鈥榓ggregation鈥�, of misshaped proteins and lead to serious diseases.

Our approach shows the importance of considering the mechanisms of diseases as not just biological, but also physical processes

Peter St George-Hyslop

Steven Depolo

Jello Cubes

探花直播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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Peter St. George-Hyslop chosen as laureate of the 2014 Dan David Prize

bjb42 — Tue, 11 Feb 2014 09:10:40 +0000

探花直播Dan David Prize,聽 endowed by the Dan David Foundation and headquartered at Tel Aviv 探花直播, recognises and encourages innovative and interdisciplinary research that cuts across traditional boundaries and paradigms. It aims to foster universal values of excellence, creativity, justice, democracy and progress and to promote the scientific, technological and humanistic achievements that advance and improve our world. 探花直播prizes are granted to individuals or institutions with proven, exceptional, distinct excellence in the sciences, arts, and humanities that have made an outstanding contribution to humanity on the basis of merit.

Three prizes of S$ 1 million each are awarded, to be shared by the laureates, for fields chosen within the three Time Dimensions 鈥� Past, Present and Future. Ten percent of the award is donated as scholarships to doctoral and post-doctoral students doing research in one of the selected fields.

Professor Peter St. George-Hyslop of the Cambridge Institute for Medical Research has been chosen as laureate of the 2014 Dan David Prize, together with Professor John Hardy of 探花直播 College London and Professor Brenda Milner of McGill 探花直播, for their work on memory and disorders of memory.

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New funding to untangle Alzheimer鈥檚 disease

bjb42 — Tue, 01 Dec 2009 09:24:18 +0000

Funding from the Wellcome Trust (WT) and Medical Research Council (MRC) has been announced for a 拢5 million research programme on Alzheimer鈥檚 disease (AD) in Cambridge. 探花直播programme, which is led by Professor Peter St George-Hyslop in the Cambridge Institute of Medical Research and Department of Clinical Neurosciences, is a major collaborative effort involving 15 scientists from seven research departments across Cambridge. 探花直播programme also involves scientists from the 探花直播 of Bristol, the Max Planck Centre for Structural Molecular Biology in Germany and the 探花直播 of Toronto in Canada.

AD is an increasingly common neurodegenerative disease of the brain that affects individuals in mid-to-late life, impairing intellectual function and memory. 探花直播disease, which is incurable, results when certain proteins in the brain become misfolded and form tangled masses that are toxic. 探花直播resulting progressive loss of cells in the brain gradually incapacitates patients for up to a decade before death. 探花直播incidence of AD is on the increase as populations live longer: in the UK, 700,000 people currently live with dementia, half of whom have AD; in 30 years' time, the estimates are that this number聽will have hit 1.4 million and be costing the UK economy 拢50 billion per year.

Professor St George-Hyslop explained the unique challenge the disease poses: 鈥楢lthough AD has been known about for over a century, it鈥檚 such a complex disease that attempts to understand the underlying mechanism using conventional tools have yielded confusing and conflicting answers. As a consequence, there is currently no drug that can halt its progression.鈥�

To plug the gaps in knowledge, the interdisciplinary research programme builds on a collaboration that has been growing for several years in Cambridge, as co-investigator Professor Chris Dobson from the Department of Chemistry explained: 鈥楢 fascination with how the fundamental molecular events that underlie AD relate to what is happening in living systems has brought together a group of people with interests that range from theory to therapy.鈥� 探花直播consortium pulls in expertise from biochemistry, genetics, clinical neuroscience, medical genetics, chemistry, chemical engineering, neurophysiology, physics, biophysics and pathology.

探花直播programme aims to lay the basis for both the development of biological markers to detect disease at an early stage, before widespread damage has occurred, and the creation of effective therapeutics. 鈥楢lready, the consortium is working well. 探花直播atmosphere takes alight as people throw in ideas about novel experimental approaches using tools from both physical and life sciences that would not have been possible until very recently,鈥� said Professor St George-Hyslop.

Professor Patrick Sissons, Head of the School of Clinical Medicine and Regius Professor of Physic, added: 鈥楾his initiative exemplifies the power of collaboration between internationally leading investigators who can look beyond their individual spheres, and work at the boundaries of traditional disciplines to bring new insight to a notoriously complicated disease.鈥�

For more information, please contact Professor St George-Hyslop (phs22@cam.ac.uk).

A major new drive to understand, diagnose and treat Alzheimer鈥檚 disease has begun in Cambridge.

Credt: orphicpixel from flickr

Tangled rope

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