NIHRDataInsights/HRCSData huggingface dataset:
Title: A neuronal model of memory - integrative processing in the retrosplenial head direction system
Funder: Medical Research Council

Abstract: Despite decades of research, the neural basis of memory formation remains little understood. One reason is that the main target of past studies, the hippocampus, is complex, multimodal and anatomically inaccessible. This proposal will study an alternative more tractable model, the head direction (HD) system, a network of peri-hippocampal structures which compute a representation of directional heading. The HD signal is critical for both spatial representation/navigation and memory formation, and is itself is capable of learning. These features make it an exciting candidate for studies of the cellular underpinnings of memory formation, critical for understanding not only memory but also its clinical correlates including Alzheimer?s disease. This proposal will focus on the largest and most accessible HD area, the rat retrosplenial cortex (RSC), located at the convergence of descending cortical and ascending brainstem streams We will test the hypothesis that the RSC acquires, computes and subsequently retrieves information about static directional cues (landmarks) which is combined with self-motion cues to provide a continuously updated representation of heading. The research outcome will be an experimental model of mammalian memory formation, plus an understanding of some of its component processes. Additionally, the project may yield a new understanding of other roles of RSC, which ? despite its size and importance in memory ? is little understood. Using chronic single-neuron recordings from rats foraging in cue-controlled environments, the integrative processes mediated by retrosplenial system will be investigated as follows: (1) Integration of visual features ? What do HD cells ?know? about visual cues? These experiments will test the hypothesis that RSC HD neurons are sensitive to higher-order visual features such as shape and pattern. (2) Spatial integration of visual cues ? Are HD cells sensitive to relative spatial location? The spatial position of configurations of landmarks will be varied to determine whether the RSC HD cells are sensitive to spatial as well as visual characteristics of landmark arrays. (3) Where (in the brain) and how is new landmark information added to the representation? Experiments involving addition of new landmarks will determine whether RSC cells can acquire such information, and attempt (using excitotoxic lesions) to determine whether the location of the memory trace is in the RSC itself. (4) How are static (landmark) and dynamic (self-motion) inputs integrated? These experiments will explore, using multi-electrode array technology, how ensembles of HD cells act as a collective, and test existing hypotheses about ?attractor dynamics? in memory formation and updating.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Neurology
Funder: Medical Research Council

Abstract: This programme, based at Imperial College London, targets the use of positron emission tomography (PET) to image the functional changes associated with Alzheimer‘s, Parkinson‘s, and Huntington‘s diseases. In subjects who have amnestic mild cognitive impairment and so are at risk of progressing to dementia the time course of amyloid deposition and microglial activation (inflammation) and relationship between these pathologies is being examined. Brain imaging findings with PET are being correlated with amyloid and cytokine levels in spinal fluid and plasma proteomic profiles. The time course and pattern of amyloid deposition in carriers of gene mutations predisposing to Alzheimer‘s disease (presenelin and APP) is also being tracked. The efficacy of anti-amyloid strategies such as passive immunotherapies is being trialled using PET amyloid imaging as a proof of mechanism. Parkinson‘s disease (PD) patients with memory or gait difficulties are also at risk of developing dementia. Again, the prevalence of cortical microglial activation and amyloid deposition in these high risk cases and the relationship between these pathologies is being examined. Asymptomatic LRRK2 and glucocerebrosidase A gene mutation carriers at risk for PD are also being ascertained to determine the time course of inflammatory changes in the brainstem. PD is also associated with other non-motor problems such as sleep disorders, fatigue, depression, and impusle control disorders. PET is being used to study the relative contributions of brainstem and limbic dopaminergic and serotonergic dysfunction to these syndromes in PD in the belief that it may throw light on the mechanisms underlying these problems in the general population. The implantation of fetal midbrain cells into the putamen of advanced PD patients has previously been associated with variable efficacy and disabling graft-associated involuntary movements (dyskinesias). We are studying the mechanisms underlying development of these dyskinesias. Additionally, a trial using PET to measure graft function in transplanted patients with early rather than advanced PD is underway. Huntington‘s disease (HD) gene carriers inevitably develop symptoms but it is now possible to detect functional changes with PET some years ahead of clinical disease manifestation. The programme is examining the time course of striatal microglial activation in asymptomatic HD gene carrtiers and how this correlates with spinal fluid and plasma levels of cytokines and other inflammatory markers. The role of cannabinoid CB1 radioligands as markers of striatal degeneration in HD is also being explored. In summary, this MRC programme is designed to determine the efficacy of functional imaging as a prognostic biomarker of dementia, to determine the role of microglial activation in driving neurodegeneration, and to provide proof of mechanism when putative neuroprotective and restorative therapies are being trialled.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Glucocerebrosidase deficiency and Parkinson’s disease: molecular mechanisms
Funder: Parkinson's UK

Abstract: Glucocerebrosidase1 (GBA1) mutations in both homozygous and heterozygous forms confer a 5 to 20-fold increased risk for the development of Parkinson's disease (PD). Heterozygote GBA1-associated PD is clinically and pathologically indistinguishable from 'idiopathic' PD. The mechanisms by which GBA1 mutations increase the risk for PD are unknown. We hypothesise that GBA1 enzyme deficiency induces defects in bioenergetics and protein handling, and amplifies these pathways in PD pathogenesis. We will investigate the biochemical consequences of GBA1 deficiency in brain tissue from PD patients with and without GBA1 mutations, and in the homozygote and heterozygotes of a GBA1 knockout mouse model with severe and intermediate deficiency of brain GBA1 activity respectively. Brains from GBA1-positive and GBA1-negative PD patients, and GBA1-negative controls (n=17 all groups) will be analysed for assays of GBA1 and mitochondrial activity, free radical mediated damage and lysosomal function in selected brain regions. The homozygote GBA1 knockout mice will be studied up to 14 days and heterozygotes to 18 months. Studies on knockout mice and their controls will include brain pathology, assays for striatal dopamine and metabolites, brain mitochondrial function, free radical mediated damage and lysosomal function. Primary cortical neuron cultures from these mice will enable us to investigate mitochondrial function including calcium homeostasis at the single cell level. Knockout mice will be transfected by adeno-associated viral vector alpha-synuclein with CNS expression and studied by the pathological and biochemical parameters discussed above to determine the potentially deleterious synergy of GBA1 deficiency and alpha synuclein expresion on protein aggregation and neuronal survival.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Are astrocytes required for optimal survival of ES cell-derived dopaminergic transplants?
Funder: Parkinson's UK

Abstract: Parkinson's disease is caused by the death of dopamine nerve cells (neurones), in a region called the 'substantia nigra'. Transplants of corresponding cells from a fetus into patients' brains has been shown to bring substantial benefits in some cases. However, due to the scarcity of such tissue, this treatment will never be widely available unless a renewable source of cells can be found. Embryonic stem (ES) cells could provide such as source, as they are unspecified cells, which can multiply in culture to produce large numbers of cells, and scientists are now able to 'direct' these cells to become dopamine neurones. However, when transplanted into animals, such neurones do not survive or function as well as their counterparts from the fetus. We propose that support cells, called 'astrocytes', are required to ensure that the transplanted neurones survive. The astrocytes found in the developing substantia nigra are known to provide specific factors required for dopamine neurone survival, but such astrocytes are probably lacking in cell transplants produced from stem cells. The experiments proposed in this application will test whether astrocytes are necessary for graft survival. We will examine how astrocytes and dopamine neurones interact and mature together in ES cell derived grafts compared to fetal grafts and whether ES cell derived grafts can be rescued by adding astrocytes from other sources. It is anticipated that this can bring stem cell derived grafts one step closer to clinical application.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Identification of small molecule inhibitors and activators of Parkin mitochondrial activity
Funder: Parkinson's UK

Abstract: Mutations to the gene encoding the ubiquitin-protein ligase, Parkin, are the cause Autosomal Recessive - Juvenile Parkinsonism (AR-JP). We have recently published details of a simple cell-based screening assay of Parkin activity that is dependent on its ability to interact with depolarised mitochondria thereby promoting mitophagy and cell death (Morrison et al. 2011). It is amenable to high-throughput screening for either activators or inhibitors of this activity. Ligase-deficient mutants of Parkin are not active, and 26S proteasome inhibitors block the activity. The primary aim of this application is to use this assay to screen a chemical library of approximately 25,000 compounds both to identify inhibitors of this Parkin activity, and others that promote the activity of ligase-deficient Parkin mutants associated with AR-JP. In principal, we have demonstrated that it is possible to 'activate' mutant Parkin using the chaperone HSJ1a (Rose et al. 2011). In this current study, follow up experiments will focus on which part of the mitophagic pathway is affected by 'active' compounds, and the design of derivatives to increase activity. Dietary administration of inhibitors of Parkin activity would be particularly useful to develop in vitro and in vivo model systems to discover if loss of Parkin mitochondrial activity at defined ages exacerbates the toxic effects of other PD-associated proteins such as alpha-synuclein, or chemicals known to produce Parkinsonian-like symptoms such as MPTP or rotenone. By contrast, compounds that promote the activity of mutant Parkin isoforms would represent potential therapeutic agents for AR-JP (and possibly sporadic disease).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Filling the genetic gaps- exome sequencing in Parkinson's disease
Funder: Parkinson's UK

Abstract: Through this UK PD consortium we have a large series of extremely well characterised Parkinson's cases in which we have DNA available. The consortium has previously been able to use these resources to identify novel genetic risk factors for PD (recent papers in Lancet and Plos Genetics). We have also a long-standing interest in familial forms of disease and the principal aim of this project is to apply exome-sequencing technologies to this valuable clinical resource. To this end we have now established a large series of young onset cases, sibling pairs and individuals from families with clear autosomal dominant and recessive inheritance. These families are too small to be used for classical linkage analysis but given the potential of exome sequencing provide a large sample size on which to perform gene discovery. We plan to sequence the exomes in 300 highly selected 'familial' PD cases. The infrastructure, including equipment, identified and sampled cases, statistical and bioinformatic analyses are already in place and the grant is to fund the acquisition of sequence data. We believe that this is a very timely grant to build on the successes of genome wide association studies and fill the genetic gap by identifying a large proportion of the remaining genes for PD. At the conclusion we will be able to deliver a much more complete picture of the architecture of the genetic contribution to PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Learning and Consolidation in People with Parkinson's
Funder: Parkinson's UK

Abstract: Motor consolidation is now recognized as an important aspect of long-term retention of motor memories. This type of 'off-line learning' allows motor skills to be retained and strengthened over time. Areas such as the basal ganglia, cerebellum, and motor cortex have been implicated in these motor learning processes. Many studies have tested people with Parkinson's on such tasks, such as prism adaptation, often showing an ability to learn in the short-term just as well as controls. However, there is limited data looking at longer-term retention of these motor skills. This is surprising, given that physical rehabilitation in Parkinsonism often improves deficits at the time of training, but this may not be sustained over the long-term. The gradual decay of learned motor skills over time has perplexed rehabilitation experts for years and limits therapeutic benefit. We hypothesize that early consolidation is deficient in Parkinsonism, preventing motor memories from being chronically established. To pursue this hypothesis we will test subjects on two procedural learning tasks: a visuomotor rotation joystick task, and a non-motor mirror reading task. Subjects will be tested before and after one hour, allowing sufficient time for short-term consolidation. We will also use an interference paradigm to disrupt initial learning and allow us to ascertain the strength of this motor memory. If our hypothesis is correct, this will allow us to characterize the deficit in consolidation, opening up the way for interventions that overcome this impairment and allow the benefits of rehabilitation to be better sustained over time.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Exosome mediated RNAi delivery in animal models of Parkinson's disease
Funder: Parkinson's UK

Abstract: Two major barriers to the successful development of therapeutic agents for Parkinson's disease (PD) are the absence of disease-relevant animal models and the inability to deliver therapeutics systemically across the blood brain barrier (BBB) directly to affected areas of the brain. In this project we will investigate a novel exosome biological nanoparticle technology developed in the Wood Laboratory 1(Alvarez-Erviti et al. Nature Biotechnology 2011) to deliver drugs, including therapeutic RNAi drugs, targeted to reduce expression of alpha synuclein, systemically across the BBB in novel transgenic &quot;humanised&quot; mouse models developed in the Wade-Martins Laboratory. Exosome-based delivery technology is the first successful method developed for systemic RNAi drug delivery to the brain. Exosomes derived from primary dendritic cells and targeted across the BBB via the expression of rabies virus glycoprotein fusion peptides represent a ground-breaking new technology and paradigm-shift for the delivery of RNA and other drugs systemically to the brain. Humanised alpha synuclein mice express either the A30P mutant or wild-type alpha-synuclein protein from the complete 135 kb human genomic SNCA locus on a pure-bred mouse Snca-/- background to preserve correct spatial and temporal regulation of expression. These are the first transgenic models to show strong SNCA transgene expression in dopaminergic neurons in the nigro-striatal pathway coupled with a reduced release of dopamine after physiological stimulation and a progressive age-dependent loss of dopaminergic neurons. They therefore provide an excellent model of early-stage PD to validate RNAi-mediated knockdown of alpha-synuclein using exosome nanotechnology as a therapeutic strategy to correct PD.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Understanding the pathogenesis of VPS35 mutations using Drosophila and human cells
Funder: Parkinson's UK

Abstract: Mitochondrial quality control (mitoQC) is an important process that preserves long-term neuronal survival. We hypothesize that VPS35, recently linked to autosomal dominant inherited PD, plays a role in mitoQC and mutations in VPS35 cause mitochondrial disruption. We will address this using molecular and genetic methods to generate and analyse cell culture and Drosophila models, which have previously proven remarkably informative. Here, using the powerful genetic tools available in Drosophila, we shall generate transgenic animals that express mutated forms of VPS35 and characterise their contribution to pathogenesis. We will determine whether VPS35 mutations leads to selective neuronal vulnerability and motor deficits in Drosophila, and importantly whether these mutations confer dominant-negative or toxic gain-of-function properties. Vps35 has recently been linked to the transport of vesicles from mitochondria to peroxisomes as part of mitoQC. Using the Drosophila models we shall test whether VPS35 mutations genetically interacts with other PD genes involved in mitoQC, PINK1 and parkin. Then, using cultured HeLa cells as well as fibroblast cells taken from 'VPS35 patients' we shall determine specifically whether mutant Vps35 interferes with the formation or transport of these mitochondria-derived vesicles and whether this leads to mitochondrial network dysfunction. We further hypothesise that these vesicles may mediate degradation of mtDNA, among other components, and shall seek evidence for this novel mechanism. Together these approaches provide a new simple animal model to further out understanding of the genetic causes of PD, and determine whether Vps35 dysfunction may be another factor that affects mitochondrial homeostasis to trigger pathogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mitochondrial function in sporadic Parkinson's Disease
Funder: Parkinson's UK

Abstract: Background: There is strong evidence for mitochondrial dysfunction in at least some subtypes of familial Parkinson’s Disease (f-PD). However, the prevalence and aetiology of mitochondrial dysfunction in the more common sporadic form of PD (s-PD) is largely unknown. Pilot data: We have previously described mitochondrial dysfunction in fibroblasts of f-PD patients. We then showed that Rapamycin-mediated activation of 4E-BP rescues mitochondrial function and have identified novel compounds with a dramatic rescue effect on mitochondrial function in parkin-mutant fibroblasts. Overall aim: To characterize mitochondrial dysfunction in s-PD, identify the underlying mechanisms and undertake rescue experiments in patient tissue. Specific objectives (methods): 1. Assessment of mitochondrial function and morphology in fibroblasts of 100 s-PD patients (High-throughput biochemical and morphological analysis, already established); 2. Exposure of all those s-PD fibroblast cultures with normal baseline mitochondrial function to toxins (rotenone or paraquat with subsequent assessment of mitochondrial function and morphology) to identify patients with increased susceptibility; 3. Quantification of PGC-1alpha mRNA (Q-PCR) and 4E-BP protein levels (Western blots of phosphorylated vs non-phosphorylated 4E-BP); 4. Rescue experiments with Rapamycin and “top hits” from our own compound screen (pre-treatment for 24h at established doses) Patient recruitment: s-PD patients are already being recruited and skin biopsies already being taken as part of the Oxford Monument study. Expected outcome: Our study will give a better understanding of the prevalence and underlying causes of mitochondrial impairment in s-PD, provide insight into mechanisms and determine whether mitochondrial rescue compounds efficient in parkin-mutant patient tissue are also effective in s-PD.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Synaptic protection with Wnts, a novel therapeutic approach for Parkinson’s Disease
Funder: Parkinson's UK

Abstract: Parkinson's disease (PD) is characterized by a progressive neurodegeneration of dopaminergic neurons in the substantia nigra through a poorly understood process. Recent studies suggest that synaptic loss in the striatum might contribute to functional decline and neuronal degeneration in PD. Thus, understanding the mechanisms that protect mature synapses is crucial for developing new therapeutic strategies for the treatment of PD. We have demonstrated that Wnt secreted proteins promote synapse formation and are required for synaptic maintenance. We have recently generated a transgenic mouse line that inducibly expresses a secreted Wnt antagonist. Expression of this antagonist in the adult striatum induces a decrease in the number of excitatory and inhibitory synapses and in the levels of dopamine receptors without affecting neuronal death or axonal retraction. These findings strongly suggest that Wnt signalling could protect striatal synapses and therefore suppress neuronal degeneration characteristic of PD. In this proposal, we will evaluate the in vivo role of Wnt signalling in the striatum and its protective/restorative properties in animal models of PD using a combination of cell biology and behavioural approaches. Specifically, we will examine i) the role of endogenous Wnt signalling components in synaptic maintenance; ii) whether compromised striatal synapses contribute to dopaminergic neuron death; iii) if protection of striatal synapses with Wnts prevents dopaminergic cell death and; iv) whether Wnts restore striatal function after degeneration in mouse models of PD. Our studies will provide the bases for developing new therapeutic strategies for the treatment of PD.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL