NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigation of the mechanism of CHMP2B-induced neurodegeneration using a novel transgenic mouse model
Funder: Medical Research Council

Abstract: The neurodegenerative diseases cause a devastating social and economic burden which will increase further as the population ages. No disease-modifying therapies are currently available, implying an urgent need to better understand neurodegenerative disease mechanisms in order to provide the foundation for therapeutic interventions. Mutations in the CHMP2B gene cause frontotemporal dementia, and affect two key cellular degradative pathways that converge on the lysosome: the endosome-lysosome pathway and autophagy. Both pathways have been implicated in a range of neurodegenerative diseases, suggesting that defining the mechanisms of CHMP2B-induced neurodegeneration will have broad impact for our understanding of neurodegenerative disease pathogenesis. However, how impairments in these central degradative pathways lead to selective neuronal dysfunction is unknown. This is a fundamental question as gaining insight into neuronal vulnerability is a key step for developing mechanism-based therapeutics. We have developed the first mouse model of CHMP2B-induced neurodegeneration, which recapitulates key aspects of human pathology. We will analyse endosomal and autophagic trafficking in primary neuronal cultures from these novel mice, in order to gain insight into the specific functions of these pathways that are required for neuronal survival. We will couple this analysis with state-of-the-art mass spectrometry to determine the specific proteins that accumulate due to impairments in these pathways. These insights should identify novel mechanisms that can be targeted therapeutically in a wide range of neurodegenerative diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Oxidative DNA Damage and Transcriptional Impairment in Brain Ageing as an Early Contributor to Cognitive Impairment
Funder: Medical Research Council

Abstract: Oxidative stress is important in brain ageing and Alzheimer's disease (AD) but the relationship to cellular dysfunction and AD progression remains unclear. In a population-representative autopsy-brain sample from the MRC Cognitive Function and Ageing Study (CFAS), we have shown that oxidative stress and DNA damage occur in some individuals with little AD-pathology, suggesting that oxidative stress contributes to cognitive decline by promoting neuronal dysfunction in some individuals independently of AD. AD pathology does not explain all of dementia in a population setting, particularly in the oldest individuals and current approaches based on removing AD molecular pathology have had limited success, suggesting an urgent need to understand the role of "non-classical" cellular pathologies. We propose that chronic oxidative DNA damage may impair neuronal function by altering the neuronal transcriptome, by down-regulation of transcription and by induction of senescence mechanisms At a population level we propose that neuronal dysfunction due to oxidative DNA damage explains a proportion of dementia, especially in the oldest old. We plan to determine the variation in oxidative DNA damage, particularly in individuals in the population without AD using the CFAS population-neuropathology cohort. We will determine the effect of oxidative DNA damage on the neuron in both CFAS and in a neuronal culture system and using markers of senescence and microarray gene-expression analysis to determine the effect on transcription. Bioinformatics approaches will allow determination of the effect of chronic oxidative stress on cellular pathways, whist time-course analysis in the cells will allow determination of how the neuronal response changes. This study will define the contribution of oxidative stress to dementia at a population level and identify altered cellular pathways reflecting neuronal injury and adaptation response that will lead to novel avenues for investigation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Defining the striatal dopamine signals that enable movement: a high resolution spatiotemporal characterisation
Funder: Medical Research Council

Abstract: Mesostriatal dopamine (DA) neurons switch their activity between low, 'tonic' firing frequencies and intermittent, 'phasic' bursts of high frequency action potentials. The intermittent, phasic release of DA within the limbic-associated ventral striatum is important for signalling reward predictions and reinforcement learning. Phasic DA release here seems particularly important for initiating reward-seeking movement. The motor-associated dorsal striatum suffers the most profound DA loss in the movement disorder Parkinson's disease (PD), but it is poorly understood whether phasic DA release here participates in behaviours, whether these be reward-seeking, or other reward-unrelated movements that are affected in PD such as habitual movement. We shall address the importance of phasic DA release in vivo in (i) 'motor' striatum for voluntary movement and in (ii) 'limbic' striatum for movements unrelated to reward. We will use fast-scan cyclic voltammetry to identify DA release in motor versus limbic striatum during movements which depend differently on these regions and on reward. DA will be detected simultaneously from both regions during reward-seeking, habit performance and unrewarded locomotor movement in mice. We will also explore how phasic DA release is regulated presynaptically by interactions with striatal ACh networks in vivo, by using ligands for ACh receptors that are known to modulate phasic-like DA release in vitro. These timely experiments should allow us to define the roles of striatal phasic DA in movement and of striatal ACh in influencing discrete DA signals in vivo. This work should offer unprecedented insights into how dysfunction of DA signals could underlie disorders such as PD and addiction. A better understanding of discrete DA signalling during movement could in turn be highly influential in guiding the design of improved DA-based therapies e.g. discrete strategies to boost phasic versus tonic DA levels.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating the neural substrates of saccadic plasticity and the mechanisms of transcranial direct current stimulation.
Funder: Medical Research Council

Abstract: Recent studies have demonstrated that reactive and volitional saccades are under the control partially segregated mechanisms and that these mechanisms are to be found in physically separate parts of the brain. The segregation is also seen in the plastic mechanisms that underpin the adaptation of these classes of saccades. We will use a classic double step saccade paradigm to induce adaptation in both reflexive pro-saccades and voluntary scanning saccades. To investigate the functional localisation of plasticity TMS will be used to temporarily interrupt the function of the parietal and frontal eye fields and the cerebellum. The study will investigate whether interruption of these sites has a specific effect on one or other class of saccade. Cells in the cerebellum change their firing patterns during adaptation of reflexive pro-saccades in a way that could drive the adaptation. It is thought that outward adaptation (saccade size increases) is caused by excitatory, whereas inward adaptation (saccades size decrease) is caused by inhibitory processes. TDCS can be applied in a configuration with inhibitory and excitatory consequences respectively on the underlying neural tissue. We will use TDCS applied to the cerebellum to test the effect of increasing inhibition or excitation on the production of inward and outward reactive saccadic adaptation - we predict a double-dissociation. We will also record local field potentials from electrodes implanted in the thalamic targets of the cerebellum in patients undergoing deep brain stimulation surgery during inward an outward saccadic adaptation. Recording the electrophysiological output of the cerebellum will inform us of the electrophysiolgical changes in the cerebellum; a first in the human. We will also record local field potentials from the cerebellar thalamus during rest and saccadic eye movements before and after TDCS. Doing this will allow us to understand the changes in cellular excitability induced by TDCS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Cortical Function in Visual Dependency in Patients with Chronic Dizziness
Funder: Medical Research Council

Abstract: Research objectives: To clarify the underlying neuroanatomical and neurophysiological basis of chronic dizziness, in particular the increased visual dependence observed in such patients. Background: Chronic dizziness is extremely common in neurology, ENT (ORL), audiology and old-age medicine. Chronic dizziness usually evolves from preceding acute, attacks of vertigo (rotatory dizziness) of viral etiology (vestibular neuritis) or recurrent episodes of vertigo (Meniere's disease and vestibular migraine). However, why some but not all patients with acute/episodic vertigo end up with long term dizziness is not known. A specific component of such chronic dizziness is an increase in visual dependence, that is, high levels of reliance on visual input for spatial orientation and balance. These patients are dizzier in environments with moving or complex visual surroundings, a syndrome called visual vertigo or visually-induced dizziness. In previous MRC cycles we have shown that vestibular physiotherapy including visual motion desensitization improves clinical outcomes in chronic dizziness but still the underlying anatomy and physiology of this important phenomenon is unknown. Methodology: We will measure vestibular patients' symptoms with questionnaires and visual dependence with validated psycho-pshysical techniques. We will correlate such results with novel findings from visuo-vestibular functional imaging (fMRI) and human neurosphysiology studies (transcranial magnetic stimulation). Imaging and phsyiological studies will explore the known inhibitory coupling between visual motion and vestibular areas in the brain. Experimental subjects will include acute vestibular patients + follow up, patients already with chronic dizziness and healthy controls. Application & exploitation of results: Dissemination of findings to the relevant clinical community and development of targeted therapies, including rational physiotherapies and non invasive brain stimulation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Does cellular niche affect the repair potential of mesenchymal stem cells; implications for spinal cord injury?
Funder: Medical Research Council

Abstract: Human olfactory mucosa is currently being assessed in several trials/treatment programmes for the transplant-mediated repair of spinal cord injury (SCI). This is due to the unique regenerative property of olfactory tissue and research which has demonstrated that transplants of cells from this tissue can improve recovery of function after SCI. Although transplantation of olfactory tissue in clinical trials has produced some promising data the precise mechanisms underlying these findings and the cell type that exerts this effect have yet to be elucidated. Recently, we have shown that both rat and human olfactory mucosa contain two types of cells which have the properties of stem cells, one of which was found to possess characteristics typical of mesenchymal stem cells (therefore termed LP-MSCs). Since bone marrow MSCs closely support haematopoiesis and survival of haemopoietic stem cells, we hypothesise that LP-MSCs, which are in close contact with regenerating olfactory receptor neurons, will influence aspects of olfactory ensheathing cell (OEC) cell biology and CNS repair. We have found that the human derived LP-MSCs and bone marrow (BM) derived MSCs secrete factors that promote the proliferation and morphological differentiation of rat OECs so that they have increased process extension and align with axons. In addition, LP-MSCs, but not BM-MSCs, produce a secreted factor that promotes myelination by oligodendrocyte precursor cells (OPCs). We now aim to identify the factor secreted by LP-MSCs using a proteomic approach. We will also use a rat model of spinal cord injury to determine whether LP-MSCs promote anatomical and functional repair when transplanted into contused spinal cord and whether they are more effective than BM-MSCs or OECs. These studies will provide a better understanding of the reparative potential of olfactory mucosa biopsies for spinal cord injury which will be important for future translational studies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: RNA metabolism in pathology of AOA2/ALS4 neurodegenerative disorders
Funder: Medical Research Council

Abstract: Ataxia oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4), are highly disabling disorders, characterised by neurodegeneration in the brain and spinal cord, causing progressive muscle weakness and finally atrophy, arising due to mutations in human senataxin protein. Senataxin shares homology with the yeast RNA/DNA helicase Sen1p and it has been suggested that senataxin may be involved in the regulation of gene expression. This research project will uncover molecular function of human senataxin protein using a combination of our expertise in RNA field and the cutting edge high throughput technology. In the first part of this project we will study transcriptional and RNA processing defects associated with AOA2/ALS4 mutations genome-wide. We propose that the function of senataxin in human cells is related to its RNA/DNA helicase function and its ability to unwind RNA/DNA hybrids (or R-loops) formed between nascent RNA transcripts and single stranded DNA template behind the elongating Pol II. We will investigate the effect of senataxin on genome-wide distribution of R-loops and study their contribution to the neurodegenerative phenotype, employing Solexa sequencing following DNA-immuno-precipitation (DIP-seq). Secondly, we will define the molecular functions of R-loops and senataxin in splicing regulation. Finally,we will identify novel RNA and protein senataxin-interacting partners, using mass-spectrometry and iCLIP approach, followed by the study of their function in gene expression and AOA2/ALS4 pathology. The long term goal of our work is to create a foundation for the collaboration between basic and clinical science beneficial to therapeutic advancement of AOA2/ALS4 diseases and development of novel molecular therapies, improving the health and quality of patients' life.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Is seizure a consequence of altered neural development?
Funder: Medical Research Council

Abstract: Many forms of epilepsy are the result of heritable gene mutations that influence the activity of ion channels. Many of these are single point mutations in voltage-gated Na channels that influence open times, voltage-dependency and/or conductivity to increase excitability of neurons. Two recent studies, in rat and the fruitfly, provide evidence to suggest that such epilepsies may be effectively treated by early exposure of the developing nervous system to clinically-used antiepileptic drugs. The rationale for this effect is that aberrant patterns of activity during early neural development lead to self-reinforcing cycles of instability in neural circuit formation. The prevention of such activity, by exposure to antiepilpetics, allows the nervous system to develop and better compensate for altered channel activity caused by the specific mutation resulting in a more stable behaviour in adult life. If proven, this observation may offer considerable promise for the treatment of some forms of idiopathic (heritable) forms of epilepsy. We will exploit the powerful molecular genetics of the fruitfly Drosophila to use optogentics to manipulate neural activity during neurogenesis to determine whether a critical period exists during which aberrant activity can destabilise circuit formation and lead to increased seizure-like activity postembryonically. There are also a number of well characterised seizure mutants of Drosophila that closely parallel the clinical manifestations of epilepsy in humans. We will also attempt to suppress seizure in these mutants through manipulation of neural activity during early development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mitochondrial Dysfunction and Susceptibility to Parkinson's disease: New Models of Pathogenetic Interactions
Funder: Medical Research Council

Abstract: This is an interactive, four-team research project in which complementary expertise/resources will be shared to develop animal models that better mimic pathogenetic processes in Parkinson's disease (PD). We plan to generate and utilize novel in vivo models in which mitochondrial defects enhance susceptibility to PD-like pathology. The relevance of these models is twofold. First, clinical and experimental evidence points to mitochondrial abnormalities as a key player in PD pathogenesis. Second, PD pathogenesis is likely the result of multifactorial insults that could well be exacerbated by an underlying mitochondrial dysfunction. PINK1 deficiency in mice, which causes mitochondrial and calcium abnormalities in the absence of frank neurodegenerative changes, will model a "permissive" genetic background on which the effects of other genetic/toxic challenges will be evaluated. We will not only determine if these combined paradigms result in synergistic damage but also assess specific mechanistic hypotheses, such as the role of calcium homeostasis in neurodegeneration. From the technical side, an integral component of these studies will be the use of state of- the-art imaging techniques and the generation of reporter mice. In the spirit of this COEN initiative, studies will be conducted in parallel at the four sites, and foster opportunities for longer-term collaborative efforts.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the phenotype and genetic architecture of myoclonic astatic epilepsy
Funder: Medical Research Council

Abstract: Aims: (1) Collect and deeply phenotype 20 MAE cases and record EEG in family members. - test the hypothesis that EEG abnormalities aggregate in family members and are raised compared to population prevalence. - accurately describe the neurodevelopmental phenotype of MAE. (2) Assess DNA samples from 96 MAE cases for copy number variants (CNVs). - test the hypothesis that recurrent CNVs are over represented in MAE. (3) Whole exome sequencing of a unique multiplex MAE pedigree. - test the hypothesis that a single genomic variant segregates with affectedness. Methodology: (1) Ascertainment and deep phenotyping: Twenty cases will be ascertained through clinician network. Informed consent will be obtained. The phenotyping protocol for cases will be: seizure and family history, speech and language, cognitive and neuropsychiatric profiling for autistic, attention and hyperactivity traits. 1st degree relatives will have resting and sleep EEG performed. All cases will have blood taken for DNA and RNA studies, cells and proteins. (2) CNVs: I shall use DNA samples from ascertained cases plus samples from international collaborators. Projected sample size (n = 96). DNA will be genotyped on a whole genome CNV focussed SNP platform (Illumina HumanOmniExpress-12). Individual allele data will be run through two algorithms (PennCNV and QuantiSNP) and called if detected on both. (3) I shall perform whole exome sequencing on 3 affected members in a pedigree. I shall use NGS facilities (Illumina HiScan) at the MRC SGDP, aiming for minimum 30-40-x read dept and >85% coverage. I shall filter novel variants using (i) bioinformatic tools (ii) comparing the three affected relatives. Candidate variants will then be tested for segregation in the pedigree. The description of neurodevelopmental problems will lead to improved awareness. Discovery of causative CNVs and/or genetic mutations can lead to more accurate diagnostic testing and genetic counselling.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: New metrics of brain network breakdown in the progressive aphasias
Funder: Medical Research Council

Abstract: The primary progressive aphasias (PPA) are a unique group of neurodegenerative dementias characterised primarily by language breakdown associated with focal temporal and frontal lobe atrophy. Three main syndromes are recognised: progressive nonfluent aphasia (PNFA), semantic dementia (SD) and logopenic aphasia (LPA). As cardinal examples of regional neurodegeneration in vulnerable brain networks, these disorders have attracted considerable interest, however many nosological and neurobiological problems remain unresolved. This project will investigate generic, nonverbal mechanisms of disordered information processing in PPA. A cohort of patients representing each of the major PPA syndromes will be studied cross-sectionally and longitudinally in relation to patients with another degenerative dementia (Alzheimer's disease) and to healthy older individuals. In three core experiments, neuropsychological, psychophysical, structural and functional MRI techniques will be used to address integrative processes linking perceptual, semantic and affective information in complex nonverbal sounds. These processes are likely to depend on distributed brain networks previously implicated in the pathogenesis of PPA. It is anticipated that this work will identify new metrics of abnormal network structure and function with specificity for particular PPA syndromes, and may help predict tissue pathology and suggest novel biomarkers in these conditions.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL