Gene Discovery Supports Research on MND Development


Professor Andrew Crosby, said: “We’re extremely excited by this new gene fi nding, as it is consistent with our hypothesis that the correct maintenance of specifi c lipid processing pathways is crucial for the way brain cells function, and that abnormalities in these pathways are a common linking theme in motor neurone degenerative diseases. It also enables new diagnoses and answers to be readily provided for families affected by some forms of MND.”


If confi rmed, fi ndings could lead to the use of patient samples to predict the course and severity of the condition in an individual and to monitor the effect of potential new drugs.


Andrew Crosby and Emma Baple (credit: University of Exeter)


Julien Prudent (Credit: Julien Prudent/University of Cambridge)


A team led by Professor Andrew Crosby and Dr Emma Baple, University of Exeter, has developed a hypothesis to explain a common cause of motor neurone degenerative diseases (MNDs), stemming from their discovery of 15 genes responsible for different forms of MNDs. The genes are all involved in processing lipids - in particular cholesterol – inside brain cells and their work describes the specifi c lipid pathways that the team believe are important in disease development.


Their identifi cation of a further new gene, named -‘TMEM63C’ – which causes a degenerative disease affecting the upper motor neurone cells in the nervous system, adds weight to the hypothesis that MNDs are caused by abnormal lipid (fat) processing, as it is located in the region of the cell where the lipid processing pathways that have been identifi ed operate.


Using genetic sequencing techniques to investigate the genome of three families with individuals affected by hereditary spastic paraplegia – a large group of MNDs affecting motor neurons in the upper part of the spinal cord – the recent studies showed that changes in the TMEM63C gene were the cause of the disease. In collaboration with a group led by Dr Julien Prudent at the Medical Research Council Mitochondrial Biology Unit at the University of Cambridge, the team also undertook studies to learn more about the functional relevance of the TMEM63C protein inside the cell.


Using state-of-the-art microscopy methods, the Cambridge team’s work showed that a subset of TMEM63C is localised at the interface between two critical cellular organelles, the endoplasmic reticulum and the mitochondria, a region of the cell required for lipid metabolism homeostasis and proposed by the Exeter team to be important for the development of MNDs.


In addition to this specifi c localisation, Dr Luis-Carlos Tabara


Rodriguez, a Postdoctoral Fellow in Dr. Prudent’s lab, also uncovered that TMEM63C controls the morphology of both the endoplasmic reticulum and mitochondria, which may refl ect its role in the regulation of the functions of these organelles, including lipid metabolism homeostasis.


Dr Julien Prudent, of the MRC Mitochondrial Biology unit, said: “From a mitochondrial cell biologist point of view, identifi cation of TMEM63C as a new motor neurone degenerative disease gene and its importance to different organelle functions reinforce the idea that the capacity of different cellular compartments to communicate together, by exchanging lipids for example, is critical to ensure cellular homeostasis required to prevent disease.”


The Halpin Trust, a charity supporting projects in healthcare, nature conservation and the environment, part-funded this research. Claire Halpin, the charities’ co-founder with her husband, Les said: “The Halpin Trust are extremely proud of the work ongoing in Exeter, and the important fi ndings of this highly collaborative international study. We’re delighted that the Trust has contributed to this work, which forms part of Les’s legacy. He would also have been pleased, I know.”


The new study, ‘TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia’, is published in Brain.


More information online: ilmt.co/PL/Eym9 58128pr@reply-direct.com


Star Collision Provides Insight into Origin of Heavy Elements


In 2017, Professor Stephen Smartt from the University led one of the international teams that produced a historic and ground-breaking discovery, proving that a burst of gravitational waves came from the collision of two neutron stars. Extensive analysis of the debri, led by PhD student James Gillanders and supervised by Professor Stephen Smartt and Dr Stuart Sim, revealed that these elements included strontium and zirconium, as well as the very heavy lanthanide group of elements, such as cerium and neodymium.


Collaborating with researchers from the Free University of Brussels and the GSI Helmholtz Center for heavy ion research in Darmstadt, they compiled as comprehensive an atomic data set as possible, enabling them to explore the production of the elements heavier than iron, since the origin of these elements remains somewhat a mystery in modern astrophysics.


The team calculated computer models of how light interacts with these elements on the Northern Ireland High Performance Computing Centre (HPC), hosted at Queen’s.


Researchers from Queen’s university Belfast, who have been analysing the results of a neutron star collision have succeeded in identifying some of the heavy elements that were created following impact.


James Gillanders said “By modelling the observations of this explosion, I have identifi ed the presence of some of the heavy elements in the Universe, through signatures imprinted by their atomic lines. This research helps to show that these exotic mergers are responsible for producing many of the


heavy elements that we see around us in the Universe today. We’d like to fi nd at least a few more of these objects to give us a reasonable sample size, and then model them in a similar way, using this excellent computing facility at Queen’s.”


Professor Stephen Smartt commented: “The event of a neutron star merging with another is relatively rare but the information we have been able to gather since our discovery has been invaluable – it has helped to solve some of the big questions around the origin of heavy elements in the Universe.


“Our collaboration with expert nuclear physicists in Belgium and Germany, combined with Queens’ computing facility, means we can combine extensive theoretical data with the extensive observations we took in 2017. It is detailed work that takes time, but this discovery has paved the way for 2023. That is when the gravitational wave detectors come back online for another year of observing. Our team at Queen’s will continue their quest to investigate the fi nal life stages of these incredibly dense stars and the mysteries of their origin.”


More information online: ilmt.co/PL/wXDw 58129pr@reply-direct.com


Funding Boost for Soft Matter Simulation Centre


The German Research Foundation (DFG) has approved a further four-years of funding for the joint Collaborative Research Center/ Transregio 146 on Multiscale Simulation Methods for Soft Matter Systems, overseen by Johannes Gutenberg University Mainz (JGU), TU Darmstadt, and the Max Planck Institute for Polymer Research. Established in 2014, researchers from multi-discipline backgrounds will continue developing fundamental methods for computer-aided simulation of soft matter, ranging from plastics, rubber, paper, oils and liquid crystals to biological membranes and proteins.


Professor Friederike Schmid of the Institute of Physics at Mainz University said: “If we want to better understand the behavior of these materials, this will only be practicable with the help of multiscale approaches, meaning we need to look at what is happening on a range of different scales simultaneously.”


He emphasised that the properties of many materials cannot be understood by studying their structure and dynamics at just one size and time scale; for example, materials can eventually fail after years because of what happens on the atomic scale. Soft matter is therefore an ideal testing ground for developing new multiscale algorithms and analysing properties from a mathematical perspective.


“The JGU Institute of Mathematics has made important


contributions to our fundamental understanding here, while computer science is fostering the development of computer simulations with the help of machine learning methods,” Schmid pointed out, highlighting the advantages of interdisciplinary collaboration with a clearly established basis in physics and mathematics.


Three main goals have been set for this third and fi nal funding period. Firstly, the researchers intend to further improve their fundamental techniques, which are now focused in particular on non-equilibrium and inhomogeneous systems. Secondly, they aim to consolidate results to date by testing the new algorithms in a broader class of model systems. And thirdly, they will apply the new methods to a series of challenging real-world problems they have identifi ed.


“We have already achieved a lot, but we still have a long way to go,” said Schmid. The long-term goal is to establish routine use of the multiscale techniques so that real-world applications for soft materials can be simulated. “We want to be able to make predictions on how the properties of materials will perform and suggestions on how to actually improve these. In the case of biological substances, we are interested in deciphering and precisely understanding the processes involved,” Schmid concluded.


More information online: ilmt.co/PL/kmpj 58136pr@reply-direct.com


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