NIHRDataInsights/HRCSData huggingface dataset:
Title: Amyloids in neurodegenerative diseases
Funder: Medical Research Council

Abstract: We work to understand the molecular basis of protein assembly into amyloid in neurodegenerative disease. Higher-order assembly of a small number of proteins within neurons and glia is a feature of neurodegenerative diseases. The proteins form amyloid structures enriched in repetitively stacked beta-strands. Mutations in the genes encoding these proteins lead to assembly and inherited neurodegenerative disease, demonstrating a causal role. Assemblies arise in discrete brain regions, from where they appear to propagate (spread and amplify) within connected brain networks, ultimately leading to neurodegeneration. We determine the structures of protein assemblies isolated from patient brain using cryo-electron microscopy. These structures enable the rational design of diagnostic and therapeutic compounds targeting protein assemblies and provide insights into assembly formation, including differences between diseases. We recently found that transactive response DNA-binding protein of 43 kDa (TDP-43) forms amyloid-like assemblies in the motor neurone disease amyotrophic lateral sclerosis (ALS) with frontotemporal lobar degeneration (FTLD) that are structurally distinct from amyloids formed of other proteins in neurodegenerative disease. We are currently using these methods to determine the structures of assemblies of TDP-43 and other proteins in additional neurodegenerative diseases. We also study the interactions between amyloid assemblies and brain cells at molecular resolution using a combination of cryo-electron tomography, quantitative mass spectrometry and molecular genetics. We develop in vitro, cell culture and whole-tissue models of assembly for this work. This will help to reveal how assemblies form and contribute to nerve cell degeneration, as well as why only select neuronal and glial cell populations in the brain are vulnerable and why this selective vulnerability differs between diseases. This is likely to reveal new strategies and targets for the prevention of amyloid assembly.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Interfacing with the brain for therapy
Funder: Medical Research Council

Abstract: The failure rate for new drugs targeting important central nervous system diseases remains high and investment in drug discovery in this field continues to diminish. A key problem is that current therapeutic approaches tacitly assume a static equilibrium in brain state. In contrast, we seek to identify and correct those circuit interactions that, through their moment-to-moment dynamics, underpin disease symptoms related to aberrant movement. To this end, we will focus on proof-of-principle studies in patients with two exemplar conditions, Parkinson’s disease and Essential Tremor, and leverage electrical stimulation in its different forms. Common to the therapeutic interventions that we plan to develop, whether invasive or non-invasive, is that they increase selectivity by limiting stimulation according to feedback. Increased selectivity should translate in to improved efficacy and reduced side-effects, and these will be our ultimate measures of success. The feedback used to control stimulation may be neural, as in the case of the amplitude or phase of oscillations recorded in the EEG or in depth recordings, or peripheral, as in the case of the amplitude or phase of tremor oscillations recorded by accelerometers. Non-invasive stimulation, like transcranial alternating current or peripheral nerve stimulation, or invasive stimulation delivered through deep brain electrodes, is then controlled according to the amplitude or phase of the feedback. However, the most appropriate choice of feedback signal and control policy can vary according to changing context, such as sleep or gait, and we will therefore develop flexible closed-loop control procedures that change between key contexts. In parallel, we will investigate the functional role of oscillatory activities in the cortical-basal ganglia network so as to inform our targeted therapy development for brain diseases.


Research activity codes: 5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: NEUROLOGICAL
Title: Cell and circuit substrates of normative and impaired motor operations
Funder: Medical Research Council

Abstract: The burden of disease is not borne evenly across all cell types in the brain. As such, it is imperative that the design of new strategies for treating disease progression and symptoms is informed by a mature knowledge of how different cell types fulfil their specialised roles to govern behaviour. The overall aim of this new Programme is to deliver high-resolution mechanistic explanations of the brain cell and circuit substrates of normative movement as well as impaired Parkinsonian behaviour. Focusing on the ‘motor domains’ of basal ganglia circuits in the brain, we will harness cutting-edge technologies for monitoring and manipulating neurons in vivo to provide essential new insights into how the activities and interactions of identified cell types are configured in their host circuits according to the temporal dynamics of dopaminergic signalling as well as action. As a key corollary, we will define how dopaminergic signalling arises in the basal ganglia and to what extent it is altered by factors of high relevance for early and sustained manifestations of Parkinson’s disease. We will also define how profound deficits in dopamine release, as occur in advanced Parkinsonism, impact on the cell-type-dependent encoding of behaviour in these circuits. To achieve our specific research objectives, we will couple novel and advanced analytical techniques with experimental interventions designed to probe causal interactions between specified circuit elements with high spatiotemporal precision. Our experiments will centre on the use of wild type and genetically-altered mice, with intact or comprised midbrain dopaminergic systems, the readouts from which will straddle multiple levels of function including molecular/genetic, structural, electrophysiological, neurochemical and behavioural. In capitalising on the new understanding of the activity dynamics of identified neurons gained here, we will also exploit specified cell types as novel points of entry for spatiotemporally-patterned interventions designed to not only dissect circuit function but also to correct circuit dysfunction and related behavioural impairments in advanced Parkinsonism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Structural studies on mechanisms of prion-like protein assemblies in neurodegenerative diseases
Funder: Medical Research Council

Abstract: A common feature of many neurodegenerative diseases is an apparent loss of protein quality control, resulting in the assembly of disease-specific proteins into amyloid aggregates, which is associated with neuronal degeneration. The protein aggregates can self-propagate and spread from cell-to-cell like prions and adopt different prion-like conformational strains. Alzheimer's disease (AD) is the most common neurodegenerative disease, which is characterized by the accumulation of senile plaques and neurofibrillary tangles in the cerebral cortex, composed of Amyloid-beta (Abeta) peptides and tau protein, respectively. Accumulation of Abeta is believed to be necessary for the initiation of AD. Like mammalian prions, some yeast prions, such as Ure2p, Sup35p and Rnq1p, exhibit “prion properties”. The protein quality control machinery involved in their propagation is highly conserved between mammals and yeast, which underlies the wide relevance of the study of yeast prions. Our group aims to elucidate the mechanisms of prion-like protein assembly in neurodegenerative diseases using an integrated biochemical and structural approaches, especially cryo-electron microscopy(cryo-EM). Our research is centred around two projects: Working with Dr Reilly (Programme 8) in the Unit to study the cryo-EM structures of Abeta assemblies from patient brain tissue with different AD phenotypes subtypes and from assemblies extracted from NL-F mice inoculated with these brain extracts and propagating putative Abeta strains. Secondly, we will study yeast prions, in particular [URE3] and [PSI+], which are formed by assembly of Ure2p and Sup35p, respectively using cryo-EM and MS to study the ex vivo extracted yeast prion fibrils and in vitro aggregated fibrils to study how distinct structures encipher prion strains, as well as the effects of PTMs on the yeast prion structures.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Peptide conjugated oligonucleotides for a phase I/IIa clinical trial in Spinal Muscular Atrophy
Funder: Medical Research Council

Abstract: SPINAL MUSCULAR ATROPHY (SMA) is a leading genetic cause of infant mortality due to progressive lower motor neuron death leading to muscle weakness. SMA is caused by loss of the ubiquitously expressed SMN1 gene. Patients carry the very closely related gene SMN2 which is only partially functional due to its alternative splice exclusion of exon 7. SPLICE SWITCHING OLIGONUCLEOTIDES (SSOs) are single-stranded, steric block oligonucleotides which, when directed toward splice sites of pre-mRNA, block binding of the splice enhancing or silencing proteins. A SSO (Nusinersen) which modifies SMN2 splicing to facilitate exon 7 inclusion to generate functional SMN protein has recently been approved for clinical use by the FDA and EMA. This first generation SSO does not penetrate the blood brain barrier (BBB) and is therefore administered through repeated invasive intrathecal injections. This is necessary for adequate spinal cord drug delivery but is not practical as a long-term therapy and also fails to treat systemic features of the disease, especially important in severe cases. We have developed advanced NEXT GENERATION SSOs comprising a peptide-conjugated SSO platform permitting effective systemic SSO delivery to essential peripheral tissues (e.g. skeletal muscle), brain and spinal cord and under a current MRC DPFS award have undertaken rigorous preclinical development and identified candidate peptide-PMOs (PPMO). We now propose to finalise preclinical work by defining therapeutic index in order to select lead and back-up PPMO candidates for clinical development. Lead and back-up PPMO clinical candidates will then undergo appropriate PK/PD and toxicology assessment in two species (rats and non-human primates) to allow MHRA clinical trial protocol approval. The lead PPMO compound will subsequently be evaluated for safety, tolerability and exploratory efficacy in a Phase I/IIa clinical trial in SMA patients.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Neuronal circuits for itch in the spinal dorsal horn
Funder: Medical Research Council

Abstract: Chronic itch (pruritus) is a distressing symptom of many diseases, and is often difficult to treat. However, despite its importance, relatively little is known about the spinal cord circuits that underlie itch. We have shown activating dynorphin-expressing inhibitory interneurons in laminae I-II reduces itch behaviour, and that these cells are involved in the suppression of itch by counterstimuli. In this project we will investigate the roles of 3 different classes of interneurons in spinal itch pathways. We will test the prediction that inactivating the dynorphin interneurons leads to increased itch, and we will determine whether these cells are also involved in gating pain. Excitatory interneurons that express gastrin-releasing peptide (GRP) are thought to be a key component of spinal itch circuits, and are known to receive synaptic input from pruriceptors that express MrgA3. We have recently identified somatostatin-containing afferents as a second type of pruriceptor, and we will test whether these also innervate the GRP cells. The receptor for GRP (GRPR) is expressed by excitatory interneurons in laminae I-II, and ablation of these cells selectively blocks itch. Our preliminary observations indicate that the GRPR neurons include vertical cells, which are known to innervate projection neurons in lamina I. We will further characterise the GRPR cells, by examining their responses to pruritic stimuli, testing whether they selectively innervate pruritogen-activated projection neurons, and determining whether they are the site at which dynorphin cells act to suppress itch. Finally, we will determine whether GRPR cells are critical and selective for itch, by chemogenetically activating/inactivating them, and testing whether this increases/decreases itch (but not pain) behaviour. The project will provide valuable information about spinal cord circuits that are involved in itch, and should assist in the development of new antipruritic drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Pain evoked by passive transfer of IgG from fibromyalgia patients to mice
Funder: Medical Research Council

Abstract: Fibromyalgia syndrome (FMS) is a common chronic pain diagnosis worldwide, with a prevalence of about 2.5% in the general population. FMS is characterized by chronic, widespread pain, typically in combination with other neurological symptoms, such as sleep disturbances, anxiety, depression and memory problems. FMS is more common in women than men, and much more prevalent in patients with autoimmune rheumatological conditions, e.g. rheumatoid arthritis, lupus erythematosus. Patients report very poor scores for health-related quality of life, regularly worse than is the case for other chronic pain disorders, such as neuropathic pain. The aetiology and pathophysiology of FMS are unknown, and the available therapies are of limited efficacy, and consequently, many patients seek help from alternative medicine. This project builds on our recent, original discovery that FMS is an autoimmune disorder that can be transferred from patient to mouse. This finding will produce a paradigm shift in how FMS is viewed, and will enable experimental studies of the pathophysiology of FMS. Our observations demonstrate that mice that have undergone transfer of FMS, faithfully recapitulate the sensory abnormalities experienced by FMS patients, with pressure (in paw and thigh) and cold hypersensitivity, but essentially normal sensitivity to noxious heat and to punctate stimulation with von Frey filaments. Our pilot data show that transfer of FMS produces ectopic action potential discharge in nociceptors and a gain of function of cold sensitivity in A-fibres. During this project we will identify the effects of FMS IgG in vivo (behaviourally and using in vivo Ca2+-imaging) and on sensory afferent nerve fibres in vitro. Finally, we will combine [Ca2+]i-measurements and patch-clamp investigations of isolated sensory neurons to identify the ionic mechanisms responsible for FMS induced ectopic activity and sensitization of nociceptors.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Brain architecture and connectivity at epilepsy diagnosis: markers of cognitive dysfunction and pharmacoresistance
Funder: Medical Research Council

Abstract: The aim of this proposal is to characterise brain architectural and physiological alterations using advanced MRI and EEG techniques in patients with a new diagnosis of epilepsy, and, in particular, determine whether measures of brain connectivity and networks provide insight into cognitive dysfunction and permit the prediction of future pharmacoresistance. There has been no prospective study of brain connectivity and networks in patients with epilepsy through the early course of the disorder. Newly diagnosed epilepsy (NDE) is rarely studied despite that this is a key time to understand the underlying biology of epilepsy and identify potential interventions. We will acquire MRI and resting-state EEG data in patients with a new diagnosis of epilepsy, and use state-of-the-art analysis methods to reconstruct structural and functional networks in patients and healthy controls. Targeted networks will involve thalamocortical structural and functional networks based on our preliminary data. Whole-brain networks will be investigated using connectome approaches, which we have shown to have predictive value for postoperative seizure outcome in patients with pharmacoresistant epilepsy. Patients will be followed up longitudinally to determine treatment outcome. All participants will be cognitively assessed. Based on our preliminary data, large-scale resting-state functional MRI and EEG networks will be used to determine the neural basis of cognitive dysfunction in patients. The proposed study will be the first detailed prospective study of human focal epilepsy from the point of diagnosis using brain connectivity imaging methods. We anticipate that this work will provide crucial new insights into the disorder by revealing brain network alterations that explain and predict cognitive dysfunction and future pharmacoresistance in people with a new diagnosis of epilepsy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The impact of TDP-43 on translation and the response to axonal damage in amyotrophic lateral sclerosis
Funder: Medical Research Council

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, which causes loss of motor neurons (MNs) leading to paralysis and ultimately death. The RNA-binding protein TDP-43 is a central player in ALS pathogenesis, but how its mutations and malfunction lead to disease is unknown. Published work and our preliminary data show: 1) TDP-43 is involved in RNA splicing, transport and translation; 2) axonal RNA localisation and translation is crucial for neuronal response to injury; and 3) cellular responses to stress and axonal damage are impaired in ALS. These observations converge to define my research question - I will investigate how mutations in TDP-43 impact on a MN process crucial for ALS: their response to damage. In order to do so, I will use our novel mouse model which bears a single point mutation in endogenous TDP-43 gene and develops progressive MN loss, allowing us to investigate the consequences of mutations within a physiological in vivo setting. I will combine novel experimental setups and more established approaches to address specific points: a) What is the impact of mutant TDP-43 on axonal translation? b) How does mutant TDP-43 alter the neuronal response to oxidative stress, and specifically to axonal stress? c) Does mutant TDP-43 alter response to axonal damage in vivo? d) Does the reversal of these changes impact on TDP-43 toxicity? I will use novel mouse tools and refined culture and biochemical approaches to identify MN-specific and axonal translation changes both in vivo and in vitro. I will then use a novel set-up we have devised to study the MN response to axonal stress in vitro, and perform axotomies combined with laser capture microscopy to characterise the impact of TDP-43 on axonal injury in vivo. Finally, I will use iPSC-derived MNs and post mortem material from patients to validate our findings, as this is paramount for the identification of novel pathways and potential therapeutic targets in ALS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identification of novel short tandem repeat expansions in neurological disorders
Funder: Medical Research Council

Abstract: Despite recent advance in our understanding of the genetic basis of neurological disorders, a large fraction remain undiagnosed, leaving a substantial gap in our ability of diagnose and understand such diseases. This discrepancy can in part be attributed to the fraction of human genetic variation not currently assessed in large medical sequencing studies. Short tandem repeats (STRs) are highly polymorphic, short repetitive sequences, that contribute to a large fraction of human genetic variation. Additionally, expansion mutations in STRs are a major and unique cause of neurological disorders. Our knowledge of STRs is currently limited to a few thousand, however it is estimated that there are over a million STRs in the human genome. STRs are not currently investigated in genetic studies due to technical challenges in short read next generation sequencing (NGS). Novel bioinformatics tools have recently emerged to accurately genotype STRs and to detect STR mutations with NGS. In the proposed research I aim to identify novel STR mutations in patients with undiagnosed neurological disease by: i)using the 100000 Genomes Project population as a large dataset to build a reference set of STRs in the human genome; ii) identifying potentially causative mutated alleles in patients with neurological disorders, and validate the findings using highly-curated cohorts of patients iii)use a long-read sequencing technology to obtain the full-length sequence of the newly identified large STR mutations. The proposed research will progress our understanding of STRs and their role in neurological disorders. The identification of novel mutations will deepen our understanding of these disorders, open novel avenues of research, and benefit the clinical diagnostic process and affected individuals and their families.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Spatial and temporal mechanisms controlling diverse myosin motor functions in health and disease
Funder: Medical Research Council

Abstract: Intracellular transport is driven by kinesin and dynein motors for long-range delivery along microtubules, whereas myosin motors move cargo over short distances along actin tracks, regulate plasma membrane dynamics through the actin cortex and provide flexible tethering of intracellular compartments to the actin cytoskeleton. The human genome has 39 myosin genes, which fall into 12 distinct structural families and in this programme grant we will focus on two classes of myosin motors, myosins of class I and class VI, MYO1F and MYO1G as well as MYO6. The principal aim of this research programme is to (1) identify the mechanisms involved in regulation of motor activity and cargo attachment, (2) characterise the cellular roles of MYO6-cargo adaptor complexes and (3) elucidate the function of MYO1F and G in microglia. We will investigate the mechanisms that control motor activity and cargo attachment to understand how cargo recognition, transport or tethering and finally motor-cargo uncoupling are temporally and spatially regulated within different tissues and cells. Together with our collaborators we will use biophysical and biochemical approaches to analyse motor properties in vitro. In addition we will take an integrated approach including functional studies, proteomic analysis and high resolution imaging in a range of primary cell types to investigate the specialised cellular functions and pathways that involve MYO6, MYO1F and MYO1G. This programme will generate fundamental insights into the cellular roles and regulation of myosin motors and their cargo adaptors in mammalian cells. We will investigate how defects in motor function are linked to neurodegeneration, which will provide new information on the underlying mechanisms in neuroinflammation and AD disease progression. In addition this work will offer novel insights for drug-discovery programs, as myosin motors are attractive drug targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL