NIHRDataInsights/HRCSData huggingface dataset:
Title: Driving synaptic repair in early neurodegeneration
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Synapse loss underlies the earliest symptoms in several neurodegenerative diseases; its progression eventually leads to neuronal loss. Critically, it is an early stage in pathogenesis that can be rescued (Science 2003; 302, 871-4; Neuron 2007; 53, 325-35) and is therefore a key therapeutic target for intervention. In the healthy adult brain synapses are continually lost and replaced, through structural plasticity, a process critical for repair that also underlies learning and memory. We have shown that neurodegeneration results, at least in part, from a failure of structural synaptic plasticity early in the disease process (Nature 2015; 518, 236-9). Using the paradigm of cooling-induced structural plasticity that occurs in hibernation in prion-diseased and AD mouse models (5xFAD mice and tauopathy frontotemporal dementia (FTD) mice), we: 1) showed that the capacity for synaptic repair and reassembly is impaired in several mouse models of neurodegenerative disease; 2) found that this results from failure to induce the cold shock protein, the RNA chaperone: RNA binding motif 3 (RBM3); and 3) defined the major role of RBM3 in maintaining structural plasticity and driving synaptic repair. Critically, we have shown the therapeutic potential of manipulation of RBM3 levels for neuroprotection


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identification of novel pathways that induce autophagy to enable neuroprotection
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. (Macro)autophagy is a major route for the degradation of intracytoplasmic contents, including proteins and organelles, like mitochondria. The earliest morphologically recognisable autophagic intermediates are phagophores, which evolve into double-membraned, sac-shaped structures. After phagophore edges extend and fuse, engulfing a portion of cytoplasm, they become autophagosomes, which deliver their contents to lysosomes for degradation. My laboratory discovered that autophagy is critical for the degradation of diverse toxic intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including Huntington’s disease (HD), mutant alpha-synuclein (forms of Parkinson’s disease (PD)), and tau. We discovered that autophagy-upregulating drugs enhance the clearance of such proteins and thereby attenuate their toxicities in Drosophila, zebrafish and mice (Hum Mol Genet 2002; 11, 1107-1117; J Biol Chem 2003; 278, 25009-25013; Nature Genet 2004; 36, 585-595; Hum Mol Genet 2006; 15, 433-442), a strategy subsequently validated by many groups. Now autophagy is considered an important neurodegeneration target by leading pharma companies. A major thrust of my laboratory has been to identify novel pathways regulating autophagy, as some of these may be druggable or may provide important insights into disease processes (e.g. Nat Chem Biol 2007; 3, 331-338; Nat Chem Biol 2008; 4, 295-305; Mol Cell 2015; 57, 219-234; Nature Commun 2015; 6, 8045). This programme, which is distinct from my funded/pending grants, will use cutting-edge strategies and collaborations (Emmanouil Metzakopian (Sanger Institute), Madan Babu (MRC-LMB) and Jonathan Clarke (ARUK Cambridge DDI) to identify novel autophagy-


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding the molecular basis of tau aggregation and spreading
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Aggregation of tau into hyperphosphorylated filaments is a defining feature of tauopathies, including Alzheimer’s disease (AD) and corticobasal degeneration, progressive supranuclear palsy and Pick’s disease. Tau is a highly expressed soluble microtubule-associated protein that plays an important role in the assembly and stability of microtubules. Aggregated tau is typically hyperphosphorylated and in this form it loses its physiological role of binding microtubules and it gains toxic properties. A key role of tau oligomers and filaments in neuronal dysfunction and degeneration is supported by a correlation of the distribution and severity of tau pathology with clinical phenotypes of AD and other tauopathies. Until recently, cell autonomous mechanisms were believed to be largely responsible for human neurodegenerative diseases. However, mounting evidence is now suggesting that protein aggregates involved in at least some of these diseases, including tau aggregates, are capable of self-sustaining amplification that can propagate along neuroanatomical connections, leading to disease progression from restricted brain areas in the early phase of the disease to widespread brain regions in the later stages. This phenomenon is commonly referred to as ‘prion-like’ spreading. Tau aggregates entering a cell can cause the formation of additional tau aggregates, leading to both amplification and cellular damage. Release of protein aggregates from brain cells and their uptake by neighboring cells then leads to spreading from cell to cell. Propagation of aggregates requires their release into the extracellular space, uptake by connected cells and then seeded aggregation of soluble intracellular proteins. Studying the underlying molecular mechanisms involved in seeding, amplification and spreading may thus lead to the identification of novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: CRISPR-Cas9 genetic screens fo
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Neurodegenerative diseases are characterised by progressive neuronal loss, due to a combination of environmental and genetic risk factors. However, the molecular mechanisms that offer vulnerability or resistance to stress conditions are not well understood. In Alzheimer’s and Parkinson’s disease (AD and PD, respectively) as well as other in other neurodegenerative disorders, synaptic dysfunction and loss is an early pathological effect, which is strongly correlated with cognitive impairment. Synapse loss is also a critical determinant of subsequent neuronal loss. Importantly, it is reversible and therefore a key point for intervention, as established in several mouse models. Identifying mechanisms of disease on the synaptic level may lead to novel routes of therapy. Therefore, we aim to identify genes involved in synaptic defects using human AD and PD in vitro models. Firstly, we will investigate the impact of loss of function of candidate genes associated with risk loci of AD and PD identified by GWAS on synaptic maintenance. Secondly, we will perform a genome-wide CRISPR-Cas9 arrayed screen to identify novel genes involved in synaptic maintenance under stress conditions using AD and PD in vitro models to indicate converging mechanisms in neurodegeneration. By studying both AD and PD we aim to discover commonalities and unique features of these disorders with the objective to arrive to novel therapeutics to protect synapses from disease progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying neuroprotective me
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Genomic instability (GIN) is an important feature of neurodegeneration and a hallmark of neuronal ageing (1), that if averted could lead to prevention, delay or reversal of GIN-related neurodegenerative disease, thus representing an important therapeutic avenue. Most mature neurons are non-replicative cells that need to live for 80+ years and all this time require the ability to deal with exogenous (e.g. chronic ionizing radiations(2, 3)) and endogenous (e.g. metabolic by-products; reactive oxygen species: ROS(4, 5)) factors that create DNA-damage (6). These injuries can range from simple nicks or R-loops following defective transcription to highly toxic double-strand DNA breaks (DSBs) caused by factors such as ROS and other metabolic by-products (7) that can cause breakage of the DNA. In mature neurons these lesions are counteracted by the DNA-damage response (DDR) via yet not very well-defined mechanisms (6, 8). It is proposed that failure to impede GIN formation and/or execute DNA repair will cause cell cycle re-entry, chronic inflammation, premature senescence, aggregation of proteins or cell death, processes that would lead to initiation of diverse neuropathology including loss/degeneration of motor or cognitive functions (1, 9-12). Hence, accumulation of GIN throughout healthy life represents one of the hallmarks of neurodegeneration (13) and numerous neurodegenerative diseases including Huntington’s Disease (HD), Parkinson Disease (PD)(5,14) and Alzheimer’s Disease (AD)(15), bear hallmarks of GIN build-up. Although GIN is probably a central player in neurodegeneration either in specific pathologies or aging, to date there is no comprehensive understanding of the cause-effect relationship nor there is any approved therapy to combat neurodegeneration via maintenance of genomic stability (6). On the other hand it needs to be noted that because at molecular/GIN level there is a strong negative correlation between cancer and neurodegeneration (16), finding the specific feed-back loops that are common can allow the repurposing of cancer drugs for neuropathology (8). The overall AIM of the Balmus Laboratory at UK-DRI will be to identify the genetic factors and the specific endogenous lesions involved in GIN-related neurodegeneration in mature neurons and how these molecular processes contribute to neurodegenerative disease (i.e. death via cell cycle re-entry) such as PD or AD as well as aging. Moreover, by finding genetic factors that can modify the accumulation of GIN and thus control neuronal homeostasis we aim to find the intervention points (biomarkers and druggable targets) that can protect human mature neurons from GIN built-up and thus achieve protection, delay or reversal of neurodegeneration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying the predisposing g
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Parkinson’s disease (PD) is the second most common neurodegenerative disorder and results from the loss of dopaminergic neurons from the Substantia nigra pars compacta. Currently, only limited symptomatic treatments are available. Recently, iPSC-derived models of dopaminergic neurons have been developed that appear to recapitulate native dopaminergic neurons well and models derived from PD patients demonstrate face-valid dysfunction such as an increase in alpha-synuclein release. This research programme seeks to advance our understanding of PD in three ways. Firstly, we will use single cell sequencing of iPSC-derived dopaminergic PD models to capture the gene expression pattern in each individual neuron being modelled. Through bioinformatics approaches, we can then identify dysfunctional processes and derive the order of gene expression changes through each process to better understand them. Secondly, by combining statistical genetics and gene networking approaches, we will identify both the likely causal non-coding variants within PD-risk-associated loci and the gene(s) through which these variants manifest their risk. We will then engineer iPSC-derived dopaminergic PD models to validate their disease-association. Finally, Parkinson’s patients individually vary in terms of the range of phenotypes they present, their severity and progression. To understand the molecular drivers of this variation, we have developed new methods able to derive a small number of quantitative traits that explain the much larger number of clinical observations recorded within deeply phenotyped patient cohorts. Studying these quantitative traits through statistical genetics approaches, we are able to divine the genetic drivers underlying PD patient variation which can be further investigated within our iPSC models. Across all these three themes, the ultimate goal is to create well-understood PD-relevant cell models that are suitable for therapeutic discovery and development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Astrocytes as an upstream modulator and downstream effector of neurodegenerative pathology
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Brain homeostasis involves the interactions of multiple cell types in the NGVU. Diverse neurological disorders leading to dementia are associated with a defective homeostasis, particularly of glutamate levels, redox balance, metabolism and immune status. Astrocytes perform key roles in homeostasis, including the bioenergetic and antioxidant support of neurons, neurotransmitter and ionic homeostasis,immunomodulation, and waste clearance. Pathological stages of neurodegenerative disease are associated with alterations to astrocytic phenotype associated with gene expression changes 1,2. These include increased chemokine/cytokine production (so-called 'reactive' state), and inflammatory marker upregulation, as well as increased oxidative stress and stress response genes. Moreover, reduced GLT-1 expression in AD patients points to deficits in glutamate uptake, while brain-wide disruption to glucose metabolism and redox balance in AD indirectly suggests that these functions may also be disrupted in astrocytes 1,2. While recent work has pointed to two different activated states of astroglia after ischemia vs. acute inflammation 3, the picture in chronic disease is incomplete. There is a need to fully profile the astrocytic changes in AD and other NDDs, both in post-mortem tissue and longitudinally using animal models, to pinpoint any functional deficits that arise, and the gene expression perturbations that underlie them. Equally important is to understand how astrocytes tune their homeostatic capacity to help maintain brain health over many decades.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Dissecting macroglial-neuronal crosstalk in C9ORF72 Frontotemporal dementia/ amyotrophic lateral sclerosis
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. To reduce dementias and related neurodegenerative disorders (NDD) to merely the consequence of genetic and biochemical dysfunction, invariably from a neuron-centric perspective, is to understate the highly evolved, dynamic and cellular connectedness nature of the human brain. Multiple lines of evidence from pathology, genetics, radiology and experimental systems implicate a central role for glia in (i) not only maintaining (and tuning) neuronal function in health but also, dependent on disease context, being (ii) injurious or (iii) neuroprotective1. Yet the role of macroglia (astrocytes, oligodendrocytes [OLG]) in NDD and ageing, the major risk factor for NDD, is grossly understudied. Dissecting the nature of cellular autonomy and the mechanism of macroglial-mediated influences on neuronal biology and function in health, ageing and NDD requires an integration of diverse experimental approaches. One powerful strategy is the use of human iPS technologies for in vitro as well as, following transplant, longitudinal in vivo study of human glial chimeric mice. This programme will focus on the development and use of mutant (plus gene-corrected isogenic pairs) patient-derived C9orf72 human iPS cells to study NGVU interactions. C9orf72 hexanucleotide G4C2 repeat expansion is an excellent model for studying NGVU cross-talk in NDD because: (i) it is the major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); (ii) it shares key biological pathways with other NDD; (iii) it underlies a clinical continuum of FTD/ALS with overlapping pathology; and (iv) there is strong evidence for macroglial involvement and non-cell autonomous neurotoxicity in disease pathogenesis


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Non-cell autonomous mechanisms of synapse pathology
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Neuropathologically, synapse loss correlates most strongly with the progressive cognitive decline in Alzheimer’s disease (AD). While a central role for synapses in AD pathogenesis and in the spread of pathological proteins through the brain is now well-accepted(1), we are only beginning to understand the implications of non-neuronal cells in these processes. Spires-Jones’ DRI programme is focused on the contributions of nonneuronal cell types to synapse degeneration. A large part of this work focuses on Apolipoprotein E ε4 (APOE4) which may be a crucial link between synapse degeneration, inflammation, and the wider NVGU. Students in the Spires-Jones lab have recently completed a systematic search and comprehensive review of the literature relating APOE to neurodegeneration, inflammation, and/or the spread of pathological proteins through the brain (2). The review of the 108 papers that matched our inclusion criteria shows strong evidence in the field implicating APOE4 in synapse degeneration(3, 4), neurodegeneration(5, 6), and inflammation(7-11) (examples of only a few key papers cited here). The systematic literature search also revealed key gaps in our knowledge, which we plan to address in this DRI programme. In particular, we will investigate the molecular pathways in synapses influenced by APOE genotype in human AD brain and how these affect synaptic function in mice in vivo and in human iPSC derived neuron/glia co-cultures. In addition to synapse loss influencing cognitive decline, synapses have recently emerged as the conduit for the spread of tau through the brain. In our systematic literature search, there were no data directly implicating APOE in the spread of tau through synapses, however indirect evidence from papers showing a role for APOE in synapse loss and inflammation indicate that this remains an unexplored possibility. ApoE has a role in presynaptic vesicle release, which could impact the release of tau from synapses (12). Glia may be important for this process as microglia and astrocytic end feet have the potential to clear tau as it spreads from pre to postsynaptic terminals. APOE4 has also been associated with faster cognitive decline in Aß+ non-demented individuals(13), which could be due to more rapid tau spread. There are some data indicating that APOE4 is associated with higher levels of pathological tau in CSF and brain(14, 15), but to our knowledge, the hypothesis that apoE influences tau spread has not been formally tested. This forms another key part of the DRI programme.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Linking genetic, epidemiology and metabolic phenotyping in dementia in the context of aging, environment and lifestyle
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Alzheimer’s disease (AD) is characterised by a prolonged pre-clinical phase involving Aβ deposition but without the typical symptoms of cognitive impairment and frank dementia until relatively late on in the disease process. Though there is well described genetic predisposition to AD, most notably presence of the APOE ε4 allele, known genetic factors to date explain only a small proportion of the variance in AD occurrence1. Little is known about the environmental, lifestyle and metabolic factors that, interacting with genetic background, determine who ultimately will go on to manifest clinical disease. Gaining knowledge of these risk factors is key to tackling the growing burden of AD, vascular and other dementias, as it offers the potential for lifestyle and preventive measures, and novel treatments, to delay or offset occurrence of clinical disease, with resultant gains in life expectancy and quality of life. This would be a major advance, since the current paradigm of diagnosis and treatment of overt disease is late, never-ending and largely ineffective. Furthermore it is associated with poor quality of life, high burden for carers, and an ever increasing cost for health services as the population ages. Reversing this trend by reducing the incidence and prevalence of dementia is an urgent priority.


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