In the brain and spinal cord, there are about 100 billion nerve cells, or neurons, that enable us to think, remember, see, hear, speak, feel... and move. Neurons talk to each other at connections called synapses. Motor neurons that control our movements connect to muscles at neuromuscular junctions. Communication between neurons and between motor neurons and muscle is called neurotransmission. Neurological conditions such as dementia or motor neuron disease start when communication at synapses or neuromuscular junctions becomes disrupted. When the communication is disrupted for too long, synapses and neuromuscular junctions break down, and finally neurons die off and are lost forever. In this project we want to investigate what causes synapses to malfunction and disappear in two related neurological diseases, namely amyotrophic lateral sclerosis (ALS), which is the most common form of motor neuron disease, and a form of dementia called frontotemporal dementia (FTD). ALS and FTD overlap genetically, pathologically, and clinically. Familial forms of both diseases can be caused by mutations in a number of genes including the TARDBP gene (encoding for TDP-43), and the C9orf72 gene. Mutations in the C9orf72 gene are the most common genetic cause of both ALS and FTD. The mechanisms behind ALS and FTD are varied and not well understood, but the symptoms of these diseases ultimately are the result of a failure in neurotransmission. Our previous research found that losing the C9orf72 protein reduces neurotransmission, which disrupts neuron activity and brain function in a manner similar to what happens in ALS/FTD patients. Similarly, defective TDP-43, which is present in nearly all ALS/FTD cases, also directly affects synapses. Evidence from our lab and others points to a specific part of the synapse called the presynapse as the main site of damage in ALS/FTD. The goal of this project is to understand how the presynapse is disrupted in ALS/FTD and how this causes the breakdown in communication between neuron that we see in patients. Discovering this could lead to new therapies.

Solid-state nuclear magnetic resonance (NMR) spectroscopy is arguably the most powerful technology for providing atomic-level structure and dynamics understanding of molecules and materials. The physical and life sciences communities exploit this analytical science technique extensively to address challenging issues in a wide range of systems relevant to, for example, pharmaceuticals, battery materials, catalysis and protein complexes. Importantly, the advances enabled by solid-state NMR as an analytical technique are continually increasing in line with technological progress in the development of new NMR hardware. In particular, the recent development of commercial 1.2 GHz NMR systems stands to open up exciting new directions in NMR methodological development and deliver unprecedented levels of structural, dynamic and mechanistic information. Seven 1.2 GHz NMR systems are already in operation across Europe with further systems soon to be installed in Germany and the USA. UKRI has recently invested in two such systems at the High-Field Solid-State NMR National Research Facility (NRF) at the University of Warwick, and at the Henry Wellcome Building for Biomolecular NMR Spectroscopy at the University of Birmingham. These systems are expected to be operational in the UK in 2025. The proposed project aims to optimise UKRI's substantial investment in high-field solid-state NMR spectroscopy (notably £23M in 1.2 GHz NMR) by working in partnership with fifteen internationally leading laboratories and seven industry partners. The work will focus on sharing technical and application know-how and expertise to deliver new experimental NMR methodologies and protocols, as well as new scientific insight into complex chemical systems. The project will be divided across three main classes of systems: inorganic materials, biosolids and pharmaceuticals, with researchers working in each of these fields. New experimental methodologies will be designed and investigated within the NRF itself, and also exploiting the wide range of NMR hardware and expertise available in the co-investigator team and partner institutions. As well as the main focus of ultra-high field NMR, the NRF and partner institutions will provide access to specialist NMR hardware such as very high- and low-temperature apparatus (100 - 1000 K) to enable complex structural and dynamic phenomena to be probed in greater detail. The techniques developed within the project will enable the capabilities of ultra-high field NMR to be fully realised and will lead to new atomic-level insights into systems of relevance to the wider scientific community and industrial partners. The dissemination of the research and the interaction with international academic and industry partners will help to maintain the UK's position as a world leader in solid-state NMR research.

The Collaborative Computing Project for NMR (CCPN) was started in 2000 to improve the interoperability of software for biomolecular NMR and to promote a collaborative community of software users and programmers. Over the past twelve years, the project has produced the CcpNmr suite of software for interactive NMR data analysis and integration and the CCPN data standard for macromolecular NMR. The software is now used worldwide by >1000 users. Through its conferences and workshops, CCPN also promotes best practices in both computational and experimental aspects of NMR. With this proposal we seek to continue and further expand the CCPN project and its user community. Building upon the CCPN software platform, new and emerging aspects of NMR and integrative structural biology techniques will now be targeted. For the current period, we aim to: 1. Develop a fully implemented version 3 (v3) of the CCPN software package. 2. Promote and expand the user uptake and user development of the software. 3. Facilitate the use and sharing of state-of-the-art NMR software technology. 4. Strengthen the training of people, sharing of knowledge and exchange of best-practice's by the UK NMR community. Version 3 of the CcpNmr suite has led to new, user-friendly applications like SpecView and ChemBuild. These are the first CCPN programs to use an entirely new graphical system based on the modern, multi-platform Qt libraries. During the new period, we will bring the same approach to the Analysis and FormatExchange programs. We will ensure that v3 components are easy to use, fully documented and thoroughly tested, with dedicated modules for specialized tasks and means to interact with external programs and services. This will provide flexible tools to support scientific collaborations and advance important areas such as solid state NMR, small molecule screening and metabolomics. To promote CCPN and increase user uptake, together with our partners we will embed CCPN in a broader range of scientific projects, enhancing its impact in the structural biological community. The greatly enhanced flexibility of the new code will promote dedicated program adaptation to the working procedures of individual laboratories. We plan to use the modular capabilities of CcpNmr v3 and a reorganised library of high-level utility functions to allow for more groups to start writing software for their own specific practices. To ease user uptake a dedicated Analysis Lite, optimized for simplicity rather than for complex problems, will be developed. The CCPN software will be extensively demonstrated through workshops and documentation. Together with its partners, CCPN will continue the process of software development and integration by means of direct integration of available methods or by using web-based services developed by third parties. Thus, CCPN users will have easy access to a software pipeline for biological NMR, which allows them to proceed smoothly from spectral data via resonance assignment to structure generation and database deposition. CCPN will collaborate with CCISB groups at Harwell to allow NMR to fulfill its role in biophysics and integrated science. To strengthen the UK NMR community, we will continue the successful series of UK CCPN conferences and teaching programs for (young) researchers. We will also continue the comprehensive help and support for CCPN users and participate in international efforts in knowledge sharing and exchange of best practices by efforts such as WeNMR. We will closely confer with the NMR facilities in Mill Hill, Birmingham and Warwick. Oversight of the project will be maintained by the CCPN Executive Committee, with representative members from the UK NMR community and CCPN's international Scientific Advisory Board.

Structural biology concerns the study of the three-dimensional structure of biological macromolecules and their interactions. Biomolecular Nuclear Magnetic Resonance (NMR) spectroscopy is one of three core techniques in structural biology, and highly complementary to the other two, i.e. X-ray crystallography and Cryo EM. Extracting information from NMR data has traditionally been complex and non-intuitive. Many smart and innovative tools have been developed, which unfortunately often have been disconnected and not well integrated and sometimes hard to use. For nearly two decades, the Collaborative Computational Project for NMR (CCPN) has been central in providing a connecting interface between the NMR data and many of these tools. CCPN also actively promotes the sharing and exchange of knowledge and best practices. CCPN also actively engages with the UK and international research communities in all matters relating to research funding and policies. The CCPN aims to continue its immense value to the scientific community over the next 5 years by pursuing the following specific objectives: 1. Development of software relevant for NMR CCPN will improve, maintain and expand its programmes, to provide for new functionalities, improved handling, and better speeds. Through fortnightly updates and regular new releases, we will ensure the proper functioning of the software across multiple platforms. We will continuously work on interoperability of our software with other NMR programmes and implement relevant tools for reporting and research data management. 2. NMR in support of Biological Sciences We will facilitate and implement the latest computational tools and developments for NMR data analysis, automation, structure generation and validation. 3. NMR in support of Medicine NMR metabolomics is a thriving field that generates crucial knowledge on metabolic pathways from cells to organisms, including humans. We have designed AnalysisMetabolomics to leverage its power and we will focus on tools for non-expert users, streamlined annotation, assignment, metadata and deposition in public repositories. 4. NMR in support of Industry In collaboration with industrial and academic partners, we will test and enhance applications that are useful to industry. Examples are AnalysisScreen, small-molecule (NMR-assisted) docking procedures to optimise workflows and efficiency and ChemBuild to assist with fragment-based drug discovery. 5. Outreach and training Through its active outreach programme, engaging with all stakeholders including national and major international NMR facilities, CCPN will promote the continuous exchange of knowledge, provide training and support the adoption of best practices in NMR. There is a growing body of "how to" videos available on the website. CCPN will actively continue to promote and develop community data standards (NEF), and will take a leading role in discussions on research funding and policies. CCPN will continue its crucial role as intermediary between the UK and international NMR community, by fostering contacts with (inter-)national NMR facilities, other CCPs, the international wwPDB and NEF efforts. To strengthen the UK NMR community, we will continue the successful series of UK CCPN conferences and teaching programs, our comprehensive help and support for CCPN users, participate in international efforts in knowledge sharing and exchange of best practices, and engage in training and teaching through workshops, papers and (video) tutorials. In short, CCPN will continue to make a crucial difference to the biological NMR community in different fields such as Medicine and Industry as well as its traditional base of the biological sciences by acting as a focal point for technology development, collaboration and sharing best practices. Ultimately, researchers who are empowered with the best tools have more time to make new discoveries.

The Collaborative Computing Project for NMR (CCPN) was started in 2000 to improve the interoperability of software for biomolecular Nuclear Magnetic Resonance (NMR), and to promote a collaborative community for software users and programmers. Over the past fifteen years, the project has produced the CcpNmr suite of software for interactive NMR data analysis and software integration, which is now used worldwide by >1000 users. Through its conferences and workshops, CCPN also promotes best practices in both computational and experimental aspects of NMR, thus helping to maximise the impact of biological NMR research. CCPN has a leading role in the development of a NMR data-exchange format and coordination of NMR instrumentation proposals for RCUK and BIS. With the current proposal we seek to continue the CCPN project and to further expand its user community. Hence, over the next grant period we aim to: 1. Maintain and expand the CCPN code base. 2. Expand the capabilities and versatility of the CCPN software package. 3. Facilitate NMR-based scientific developments in collaboration with the partners of the project and the NMR community at large. 4. Promote and expand user uptake and user development of the software. 5. Provide support for research data management (RDM). 6. Support the training of researchers, sharing of knowledge and exchange of best-practices by the UK and international NMR community.