NIHRDataInsights/HRCSData huggingface dataset:
Title: Interaction of Rab8 with OCRL1: Synaptic growth function in Frontotemporal Dementia and the Neurodevelopmental Disorder Lowe Syndrome
Funder: Medical Research Council

Abstract: In a genetic screen for enhancers and suppressors of a Frontotemporal Dementia related phenotype in Drosophila, we have identified two regulators of membrane traffic (Rab8 and OCRL1) that are known to physically interact. The physiological and cell biological consequence of the interaction between Rab8 and OCRL1 are as yet unknown. Rab8 is a small GTPase and a known regulator of membrane traffic at the Golgi and recycling endosome. Mutations in OCRL1 give rise to the neurodevelopmental condition Lowe Syndrome (LS). OCRL1 is a phosphoinositide phosphatase known to interact with many Rab proteins, endocytic proteins and actin cytoskeleton regulators to effect changes in membrane traffic. Due to issues of genetic redundancy, studies of Rab8 and OCRL1 have been hampered in model organisms to date. In Drosophila there are no redundancy issues for Rab8 or OCRL1. Using the advanced genetic toolbox of Drosophila we have identified mutants in Rab8 and OCRL1 and are now in a position to study: 1) the physiological, anatomical and cell biological consequence of loss of Rab8 function in neurons, 2) for the first time, study the cell biological, anatomical and physiological consequences of loss of OCRL1 function in neurons (and the whole organism), 3) the physiological role for the Rab8 interaction with OCRL1 in a whole organism. We have already observed dysregulation of TGF-beta and JNK/AP1 signaling at the larval neuromuscular synapse of Rab8 mutants. Our focus will be on the role of these two important proteins in regulation of membrane traffic at the synapse. This study will inform our understanding of membrane traffic in FTD and LS affected neurons.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Activity-dependent regulation of synaptic strength and cellular mechanisms of migraine
Funder: Medical Research Council

Abstract: Although compensatory homeostatic synaptic mechanisms caused by changes in the activity of neuronal networks are abundantly documented in experimental studies, they have been largely overlooked in studies of episodic neurological disorders (such as migraine, epilepsy, and ataxia) which are all thought to be due to de-stabilised neuronal network function triggered by disease precipitating stimuli. The main goal of this project is to investigate for the first time the role of activity-dependent homeostatic compensatory mechanisms for inherited ion channel dysfunction using two mouse knock-in models of Familial Hemiplegic Migraine Type 1 (FHM1). FHM1 manifests as severe migraine with aura and is caused by dominant missense mutations in the CACNA1A gene, which encodes the pore-forming Cav2.1 subunit of P/Q-type calcium channels, a major trigger of action potential (AP)-evoked neurotransmitter release in the brain. Using a combination of FM-dye and Ca2+ fluorescence imaging, presynaptic AP recordings, whole-cell patch-clamp recordings, and optogenetic photostimulation we will test how chronic manipulations of network activity affect the major presynaptic parameters in different types of small neocortical synapses expressing S218L and R192Q Cav2.1 mutant channels. Specifically we will address the following questions: Is homeostatic compensation of AP-evoked release in S218L and R192Q neurons mediated by (i) changes in vesicular release probability at the active zone or (ii) changes in the number of release-ready vesicles? How do S218L and R192Q affect presynaptic AP waveform? How do S218L and R192Q mutations affect excitatory transmission in different types of neuronal connections in ex vivo acute cortical slices? This should provide the first insights into the role and the limitations of homeostatic compensation for FHM1, which can be used as a novel framework to understanding the abnormal neuronal circuit behaviour in paroxysmal neurological disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: TARGETING PARKIN & MITOCHONDRIAL DYNAMICS IN HUNTINGTON'S DISEASE
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is an incurable, fatal neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (HTT) protein. This mutation causes HTT to misfold and aggregate, leading to widespread dysfunction and death of vulnerable neurons. As with several other neurodegenerative disorders, the pathogenesis of HD has been closely linked with mitochondrial dysfunction, which includes alterations in mitochondrial dynamics (e.g. increased mitochondrial fragmentation). In preliminary studies we have recently found that the Parkinson's-linked protein parkin alleviates several disease phenotypes in HD flies when overexpressed. Parkin plays a role in clearance of damaged mitochondria (mitophagy), via modulation of mitochondrial dynamics. Here we propose to further investigate the mechanisms underlying parkin protection in HD fruit flies and a PC12 cell model, and also explore the role of mitochondrial dynamics and mitophagy in pathogenesis of this disorder. We will use genetic approaches to modulate parkin expression in HD models - as well as related proteins (e.g. PINK1, Mfn, Opa1, Drp1) - and ascertain the influence upon mitochondrial phenotypes (e.g. mitochondrial morphology, mitochondrial respiration). Relatedly, as parkin has been found to participate in protein degradation and autophagy of aggregated molecules and reduce proteotoxicity, we will also explore the relationship between parkin and HTT. In total, this work will explore the protective role of parkin in HD, and interrogate mitophagy and mitochondrial dynamics in this disorder. These studies may ultimately contribute to therapeutic strategies for HD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Pain processing and pain perception in the human brain: a neural signals approach
Funder: Medical Research Council

Abstract: Evidence-based medicine requires rigorous methods to measure pain experience and its neural bases, yet these methods remain elusive. Noxious laser heat conveyed by the Adelta pathway provides a key experimental model of human pain. We focus on perceived intensity of 'pinprick' laser pain, identified by reaction times as Adelta-mediated. Noxious stimuli are presented at two preselected levels within the Adelta range. Volunteers report each stimulus as 'higher' or 'lower' intensity. Signal detection measures of d' (sensitivity) and C (bias) provide key indices of pain processing WITHIN the Adelta pathway. Different features of the EEG responses to nociceptive stimuli (e.g., N1, N2, P2 waves, gamma power) are extracted. Bisecting the amplitude distribution for each component is equivalent to a 'higher/lower' perceptual judgement, defining NEUROMETRIC d' and C. By varying cutoff values, we identify WHICH neural component best approximates perceptual sensitivity and bias. This produces a highly-controlled, pathway-specific model of pain intensity, able to distinguish bias from sensitivity at both perceptual and neural levels. Experiments 2 and 3 put the method to work. Infusions of remifentanil, or saline are given under clinical supervision in Expt 2. We investigate whether analgesia involves changes in perceptual sensitivity or bias, and associated EEG neurometric changes. Experiment 3 extends the method to placebo and nocebo conditioning. Visual cues signal impending lower or higher intensity, while neutral cues have no predictive value. We assess whether placebo/nocebo cues change perceptual and neurometric sensitivity, relative to neutral cues, or rather change biases. Neural events after the cue but before the laser could also influence pain perception. We thus investigate the interesting hypotheses that reduced pain perception under placebo is based on DIFFERENT neural signals, and not simply reduced levels of 'normal' nociceptive signals.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: NEUROLOGICAL
Title: Pathway-driven identification of therapeutic targets for combatting Alzheimer's disease.
Funder: Medical Research Council

Abstract: Our aim is to gain a better understanding of the signaling mechanisms driving beta-amyloid neurotoxicity, to identify effective and tractable novel therapeutic targets in the pathway and to develop assays suitable for future high throughput screening ready to identify small molecules acting on them. We are in a unique position to do this following our discoveries concerning the pathway activated by beta-amyloid, which mediates its neurotoxic properties including; tau phosphorylation, neuronal death, synaptotoxicity and, in vivo, cognitive impairment. This pathway, the wnt-Planar Cell Polarity (wnt-PCP) pathway, is also detectable in the Alzheimer's disease (AD) brain. Of major significance for our understanding of AD pathology, the beta-amyloid precursor protein (APP), from which beta-amyloid is derived, has been identified as a necessary component of the wnt-PCP pathway where it is needed to drive it through recruitment of Abl: Thus, the beta-amyloid induction of wnt-PCP signaling is APP-dependent! Our understanding of the pathway will now enable us to decipher it further and more fully define the roles of APP and beta-amyloid within it. We will employ a range of techniques in cell lines and neurons, and validate findings in tissues from animal models and man. In the process we will identify novel, apt therapeutic targets through which to target the disease. Our adoption of peptide array technology to rapidly and accurately map specific protein-protein interactions, will not only help pathway elucidation but will also generate binding peptides, with which, and their binding partner proteins, we will generate assay suitable for future high throughput screening. Thus at the end of this project we will be in good position to commence small molecule identification with a battery of neuron based assays in place ready to evaluate active compounds. Such undertakings will, of course, be dependent on our obtaining further funding.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Deficient Wnt signalling in synapse degeneration and its contribution to PD
Funder: Medical Research Council

Abstract: Mounting evidence suggests that synapse loss and dysfunction are early events in Parkinson's disease. Importantly, synapse vulnerability might contribute to the subsequent degeneration of dopamine neurons. However, little is known about how synapses degenerate. Several studies support a role for deficient canonical Wnt signalling in PD. To test the contribution of this signalling pathway in neuronal and synaptic degeneration, we generated inducible transgenic mice that express the secreted Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum. These mice exhibit degeneration of cortico-striatal and dopaminergic synapses accompanied by motor defects without neuronal loss. Thus, these mice provide an ideal model to unravel the mechanisms that contribute to synapse vulnerability. Our main objectives are: 1) What are the mechanisms that trigger synapse degeneration in the adult striatum? Through our high through put analyses we have identified key molecules that are affected during synapse degeneration in Dkk1 mice. We will examine the functional contribution using in vivo gain and loss of function experiments to test their function in synapse vulnerability, neuronal death and motor behaviour. 2) What is the impact of deficiency in Wnt signalling on synaptic transmission and plasticity in the adult striatum? Here we will use electrophysiological approaches to determine the impact of deficient Wnt signalling on striatal circuits using specific transgenic lines that label striatal neurons of the direct and indirect pathways. 3) Does deficient Wnt signalling increase synapse and cell vulnerability in ageing? Although ageing is a major risk factor in PD, little is known about how synapses change and become vulnerable during ageing. We will examine how deficiency in Wnt signalling in the striatum affects synapses in ageing animals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neural Oscillations in Health and Disease
Funder: Medical Research Council

Abstract: The main research question I am aiming to answer is whether altering deep brain stimulation patterns to selectively disrupt neural oscillations underlying disease symptoms can provide significant improvements in therapy by reducing treatment side-effects and improving power efficiency. 1) I will develop theoretical disease models to determine when pathological neural oscillations are most susceptible for disruption using dynamic causal modelling, a Bayesian framework for inferring neural dynamics. In order to represent neural dynamics central to disease pathophysiology, I will extend the dynamic causal modelling framework to a) capture changes in neural oscillation amplitude and phase, b) incorporate the effect of deep brain stimulation on neural oscillators, and c) model activity dependent plasticity. 2) Using dynamic causal modelling, I will identify neural networks driving Parkinsonian and Essential tremor and explore neural dynamics defining pathophysiological differences between these two tremor types. By simulating neural response to different stimulation patterns I will gain valuable insight into stimulation patterns that can most effectively disrupt pathological neural oscillations driving tremor. 3) Finally, I will experimentally test the hypothesis that delivering stimulation only when tremor-related brain activity is most susceptible for disruption can achieve significant improvements in therapy and crucially reduce side effects currently observed during continuous high frequency stimulation. To this end, I will control when deep brain stimulation pulses are delivered for therapy using active phase tracking of peripheral tremor in two patient groups: Parkinson's disease and Essential Tremor.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: Single cell and behavioural studies of entorhinal cortex and hippocampal function in a transgenic mouse model of Alzheimer's disease
Funder: Medical Research Council

Abstract: BACKGROUND. The entorhinal cortex (EC) and hippocampus (HC) are the first cortical regions to be affected by Alzheimer's disease (AD) pathology and this study will address one of the fundamental knowledge gaps in AD research by determining the effect of disease on the function of EC and HC neurons. The central hypothesis is that AD-related disruption of the EC-HC circuit results in disruption of spatially-related single cell activity and behaviour. Innovative methodologies will be used in transgenic AD mice to answer the following questions: 1. What is the effect of AD pathology on EC grid cell and HC place cell activity, and on the behavioural correlate of this activity? 2. Do disease-related alterations in grid cell activity precede alterations in place cell activity? 3. Do changes in single cell activity and behaviour correlate with reductions in EC thickness and HC subfield volumes? METHODS. Multi-electrode arrays chronically implanted into the EC and HC of TgCRND8 mice expressing a human APP mutation will be used to determine disease effect on grid cells and place cells. A novel parameterisable task will generate parametric behavioural reads to track disease progression and correlate with single cell data. Ultra high field MRI at 9.4T will yield structural correlates at subfield levels of resolution. Correlations with AD pathology will be established via quantification of amyloid-beta oligomers in CSF obtained by dialysis at the time of recording, and via immunohistochemical studies. IMPACT. This work has major translational impact. The study of these neuronal populations provides an in vivo platform for evaluating the effect of trans-synaptic spread of disease. Outputs from the behavioural work will inform the design of analogous tasks for use in patients both as a diagnostic tool for pre-dementia AD and as outcome measures for use across preclinical and clinical phases of future treatment trials aimed at delaying or preventing progression to dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying the role of neuroinflammation in frontotemporal dementia - a pathological and cerebrospinal fluid biomarker study
Funder: Medical Research Council

Abstract: Frontotemporal dementia (FTD) is a unique neurodegenerative syndrome characterised by progressive impairments of behaviour, social or language functioning. Although most patients have a sporadic form of FTD, a third of patients have an underlying mutation in one of three main genes: MAPT, C9ORF72 or GRN. We do not fully understand the steps in FTD disease pathogenesis, and there are no effective treatments. Previous research suggests a role for neuroinflammatory mechanisms in FTD, with small studies showing altered levels of inflammatory markers in brain tissue and cerebrospinal fluid (CSF) samples from patients with FTD. This project aims to identify CSF biomarkers of neuroinflammation in patients with FTD and to investigate their relationship with measures of disease severity and progression. Post-mortem brain tissue from patients with both genetic and sporadic FTD as well as healthy controls will be used initially to identify abnormalities in neuroinflammatory pathways. Assays of candidate biomarkers identified in these analyses will then be developed and tested in CSF samples from groups of patients with genetic subtypes of FTD, their presymptomatic relatives, sporadic FTD cases and healthy controls. These results will be used to examine whether such markers correlate with measures of disease severity and/or progression established from clinical and neuroimaging analyses. CSF biomarkers identified in this project, once validated, might be used to develop novel therapeutic targets, guide clinical trials of future or existing anti-inflammatory therapies, and predict more accurately progression of disease and response to treatment in sporadic or genetic forms of FTD.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: GLUTAMATE RECEPTOR ION CHANNELS AND SYNAPSE DYSFUNCTION
Funder: Medical Research Council

Abstract: Glutamate receptor ion channels (iGluRs) are essential for relaying and storing information at excitatory synapses in the brain. A considerable number of disease-linked point mutations and non-synonymous single-nucleotide polymorphisms (SNPs) in human iGluR genes have been reported and deposited in public databases. My in silico research indicates that these genetic variants are distributed within sequences coding for functionally crucial domains of the iGluR structure but their effects on synapse function are unknown. We need to understand how these sequence changes impact on iGluRs to alter synaptic function and cause disease. In this project, I will investigate the effects of disease-causing point mutations and SNPs in human iGluRs on the basic functions of synapses and response to AMPA receptor-targetting drugs. Mutated AMPA NMDA receptors will be introduced by single-cell molecular replacement into CA1 neurons of cultured hippocampal slices from established floxed iGluR mouse lines. Receptor and synaptic function will be measured in excised patches and whole-cell recording respectively. The key goals of this project are: 1) To identify human genetic variation of potential significance to AMPA and NMDA receptor function and pharmacology using bioinformatics approaches 2) To determine how synaptic transmission is altered by genetic changes in AMPA and NMDA receptors and understand the synaptic basis of disease-causing mutations 3) To evaluate interactions between AMPA receptor SNPs and allosteric modulators


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Targeting activin receptors as a novel approach to promote myelin repair in the central nervous system
Funder: Medical Research Council

Abstract: I propose to test the contribution of activin receptor signalling to oligodendrocyte progenitor (OPC) responses during myelin production/repair in the central nervous system. Aim 1: to characterize activin receptor expression in vivo by immunofluorescence during developmental myelination and remyelination (both toxin- and immune-based lesion models). Aim 2: to determine the activin receptor subtype driving OPC responses relevant for myelination and remyelination, by CRISPR-mediated genomic deletion of specific receptor subtypes and analysis of OPC responses in vitro and following transplant into myelinating and remyelinating ex vivo brain explants, and receptor-specific pathway activation assessed by phospho-antibody microarrays. Aim3: to test effects of additional ligands either known to, or predicted to, bind activin receptors on OPCs, first by assessing expression during myelination/remyelination in vivo and then screening detected ligands for their potential to stimulate OPC responses using high throughput image acquisition and signalling pathway activation as above. Aim 4: to elucidate contribution of activin receptor signalling in OPCs to myelination and remyelination, by generating a constitutive and inducible OPC-specific conditional knockout for the activin receptor required for all activin receptor signalling, respectively, and crossing to reporter mice for analysis of knockout OPCs. OPC responses and myelination will be analyzed by immunofluorescence and ultrastructural analysis. Sufficiency of activin receptor stimulation in driving remyelination will also be tested by activin receptor ligand supplementation to demyelinated brain explants (to delineate effective concentrations) and in vivo to focal lesions of the central nervous system. I envisage that this research will impact therapeutic strategies to promote myelin repair in human myelin disorders such as multiple sclerosis to decrease clinical impairments, by targeting activin receptors on OPCs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL