NIHRDataInsights/HRCSData huggingface dataset:
Title: EXPLORING THE ROLE AND THERAPEUTIC POTENTIAL OF RAB GTPASES IN HUNTINGTON'S DISEASE
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is a 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 cellular dysfunction and death of vulnerable neurons. The pathogenesis of HD has been linked to defects in intracellular vesicle trafficking due to impaired function of Rab GTPases. ~60 Rab GTPases in mammalian cells are critical for nearly every step of vesicle trafficking. We and others have shown that increased expression of Rab5, Rab8 or Rab11 protects against mutant HTT (mHTT) toxicity in cell and fruit fly models of HD. We have performed a systematic siRNA screen in mammalian cells to identify additional Rabs and related proteins that modulate mHTT toxicity and identified 8 robust candidate disease modifiers. Here we propose to define the role of selected Rabs in HD and assess their therapeutic potential. We will validate protection by candidate Rabs in fruit fly models of HD and human pluripotent stem cell-derived (hPSC) neurons and myeloid cells. We will also test the efficacy of potential Rab modulating compounds, and explore alternative targeting approaches. The extent of Rab-specific defects in HD and their mode of protection we will be assessed using a range of phenotypes in mammalian cells, fruit flies, and mice. Metrics used include mHTT expression and aggregation, autophagy, vesicle trafficking, as well as Rab activity and localisation. Interesting findings will be confirmed in hPSC derived neurons/myeloid cells, and ex vivo patient myeloid cells. In total, this work will inform the role of Rab GTPases in HD pathogenesis and better define their therapeutic potential and mechanism(s) of protection, informing strategies for exploiting their protective properties. As dysfunctional Rab activity has been implicated in several diseases these findings may have broader significance.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Molecular mechanism of NAT1.7-modulated negative regulation of SCN9A expression
Funder: Medical Research Council

Abstract: Research into the cellular and molecular processes that control the sensation of pain is a vital source of knowledge for the development of more effective analgesics. We have shown previously that loss of function mutations in the SCN9A gene, coding for the voltage-gated sodium channel Nav1.7, lead to inherited painlessness - identifying SCN9A as a key pain gene. We have recently discovered a new gene from the SCN9A locus that encodes a natural, tail-to-tail, partially overlapping antisense transcript that is conserved in humans and mice (NAT1.7). Importantly, NAT1.7 and SCN9A transcript levels show a discordant expression pattern in tissues and elevation of NAT1.7 in cell-based systems causes a downregulation of SCN9A mRNA and Nav1.7-based sodium currents. The data indicate that NAT1.7 plays a role of a negative regulator of SCN9A and has the potential to affect pain thresholds via modulating SCN9A/Nav1.7 levels. This regulation can be achieved at transcriptional and/or post-transcriptional levels, such as transcriptional interference and epigenetic silencing of the SCN9A promoter, SCN9A silencing via NAT1.7-encoded microRNAs, splicing interference, RNA editing and changes in subnuclear and subcellular localisation. This regulation is likely to control the biological function of Nav1.7, and appears to be most important in tissues such as brain, DRG, and spinal cord. In order to elucidate the mechanism of SCN9A regulation by NAT1.7, we aim to answer how, where and when does NAT1.7 downregulate SCN9A expression. We will use detailed analysis of NAT1.7 function at the molecular, cellular and mouse developmental and behavioural levels in a newly developed NAT1.7 knockout mouse model. We aim to understand the consequences of loss of NAT1.7 on molecular, cellular and behavioural levels, and assess the effects of overexpressing NAT1.7 using a viral based approach in dorsal root ganglia, with the aim that this could provide a new approach to analgesia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: ANALYSIS OF ZDHHC17 INTERACTION NETWORKS AND PROTEIN INTERACTIONS LINKED TO NEURODEGENERATION
Funder: Medical Research Council

Abstract: The zDHHC enzyme family, which is encoded by twenty-four distinct genes in humans, mediates the S-acylation of a diverse array of neuronal proteins. The importance of this enzyme family is highlighted by links between enzyme dysfunction and disorders including neurodegeneration, intellectual disability and schizophrenia. zDHHC17 is essential for neuronal function and has been linked with Huntington's disease due to its interactions with huntingtin. We have also identified this enzyme as a potential therapeutic target for the neurodegenerative disorder neuronal ceroid lipofuscinosis. However, our understanding of the physiological functions and pathophysiological effects of zDHHC17 is severely hindered by a lack of knowledge about the substrate targets of this enzyme. We have identified a novel zDHHC17 recognition motif (termed zDABM), which mediates the interaction of known substrates with this enzyme. Furthermore, we have recently defined the sequence rules of the zDABM and used this novel information to predict new substrates of zDHHC17. In this project, we will capitalise on these important breakthroughs to identify the substrate interaction network of zDHHC17 in neurons. The role of the zDABM sequence in controlling the S-acylation and localisation of the zDHHC17 substrate network will also be determined. To investigate the potential importance of the zDABM sequence in Huntington's disease, we will explore how the zDABM of huntingtin is impacted by polyglutamine tract expansion and how it contributes to the regulation of zDHHC17 S-acylation activity. Finally, we develop novel peptide inhibitors based on the zDABM sequence and test their therapeutic potential for the treatment of neuronal ceroid lipofuscinosis. Overall, this study will provide a major advance in our understanding of the physiological functions of zDHHC17 and its role and therapeutic potential in neurodegenerative diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Maximising a small vessel disease brain bank resource
Funder: Medical Research Council

Abstract: We will develop a deeply annotated tissue resource for biomedical researchers studying the pathophysiology of SVD. We will integrate a number of established clinical cohorts within the Edinburgh Brain Bank, and data detailed data linkage such that we can access primary and secondary clinical data from all patients who donate brain post mortem, and further link these with additional tests such as imaging. While there are some animal models that replicate to a degree some elements of human SVD, to truly investigate the pathophysiology of this complex and poorly understood condition, human brain tissue is required. This will allow research groups to interrogate human brain tissues generally (such as array technologies) or locally (such as laser capture microdissection) to better understand cellular events and changes, which in turn could lead to more targeted and relevant animal models. Assessment of cellular pathophysiology is enriched by direct correlation with clinical phenotype, and this is now seen as a key element of any successful human biobank- researchers need more than pathologically annotated human tissues, they need the deeper annotation delivered by linked clinical and pathological data.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: Gene therapy for Childhood Parkinsonism: Dopamine transporter deficiency syndrome
Funder: Medical Research Council

Abstract: We aim to generate robust, preclinical data to support a future clinical trial of Adeno associated virus (AAV) gene therapy for Dopamine transporter deficiency syndrome (DTDS). Our previous proof of concept neonatal AAV9.hDAT gene therapy study showed rescue of survival and locomotor phenotype in Dopamine transporter knockout (DAT-KO) mouse, but off target effects indicated that restriction of expression was required for clinical application. We will model clinical stereotactic delivery methods and validate AAV2 serotype in DAT KO mice, to control distribution of expression and progress this treatment towards the clinic. Need: DTDS is a childhood neurotransmitter disorder that causes a progressive infantile parkinsonism-dystonia and is frequently misdiagnosed as cerebral palsy. Children are severely disabled with distressing hyperkinesia and dystonia. They progressively worsen with bradykinesia and muscle rigidity termed parkinsonism. This is untreatable and results in severe neurodisability and death in adolescence. DTDS results from loss of function mutations in the SLC6A3 gene, that codes for DAT. DAT is physiologically expressed in midbrain and striatum and functions to terminate neurotransmission and uptakes dopamine for recycling. Rationale: Gene therapy for childhood neurological disorders is showing great promise. AAV2 gene therapy is used to treat a similar disorder to DTDS called Aromatic L-amino acid decarboxylase (AADC) deficiency. Children receive stereotactic putaminal injection of AAV2.AADC, resulting in motor improvement providing clinical precedent for our proposal. We aim to obtain robust preclinical proof of concept data for stereotactic delivered AAV2 gene therapy for DTDS, to support application for a clinical trial. The gene therapy aims to restore sufficient DAT activity to improve dopamine homeostasis, movement and neurodisability for DTDS children.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Engineered Potassium Channel gene therapy for epilepsy
Funder: Medical Research Council

Abstract: Refractory epilepsy is a common, severe neurological disorder, for which there are limited treatment options. We recently showed that overexpression of the human Kv1.1 potassium channel, encoded by KCNA1, suppresses seizures in a rat model of refractory focal neocortical epilepsy. The treatment was well tolerated and potentially amenable to clinical translation, but the construct used in that study was not optimal. We have now refined our gene therapy construct to use a safer non-integrating backbone (pCCL), a synthetic cell-specific human promoter (CAMK2A), and a KCNA1 sequence engineered to remove the necessity for ADAR-dependent RNA editing. In a randomised blinded trial in a rodent model of focal neocortical epilepsy, we showed that this new engineered potassium channel (EKC) construct is highly effective in reducing seizure frequency, even when administered after epilepsy has become established. We now apply for funding to produce GMP grade viral particles (M1), to carry out GLP safety and biodistribution studies at two time points (M2), and to carry out a first in human phase I/IIa clinical trial. Our proposed initial study will be carried out in patients where the epileptic focus has been scheduled for removal. If successful, the treatment will subsequently be extended to patients for whom resection is not an option because of the proximity of the focus to eloquent cortex. Finally, if approved for use in humans, our approach will open the possibility of treatment for a range of disorders associated with excessive excitability of discrete neural networks (pain, Parkinson's, migraine).


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: An integrated biochemical, genetic and transcriptomic approach to defining target therapeutic pathways in Parkinson's disease
Funder: Medical Research Council

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder that currently does not have any neuro-protective treatments. Experimental compounds have shown promise in animal models of PD but have failed to show efficacy in human clinical trials. There is a growing consensus that PD is a heterogeneous condition and this may explain some of the failures of drug trials to date. Based on previous assessment of mitochondrial function in peripheral tissues from PD patients, we hypothesise that there are subgroup of PD patients in which mitochondrial dysfunction is more prominent than others. This has important implications for the future of neuro-protective drug discovery, as trials on drugs targeting mitochondria are likely to fail in a proportion, if not the majority of PD patients. Currently there are no reliable biomarkers of mitochondrial dysfunction in PD. As such I propose an innovative approach: that firstly revisits the earlier work delineating mitochondrial dysfunction in peripheral blood cells in PD using state-of-art technology to assess mitochondrial function in live cells, and secondly integrates DNA and RNA data from the same patients to develop robust and accessible biomarkers for mitochondrial dysfunction. I will use a comprehensive battery of mitochondrial function tests (including oximetry, mitochondrial membrane potential and total ATP levels) to assess mitochondrial function in lymphocytes from PD patients, both with and without mutations in genes from mitochondrial pathways known to cause PD - PARK2/PINK1. These data will be compared to age and sex matched controls. From this data I will define a subset of PD patients with mitochondrial dysfunction who will go on to have in depth clinical, genetic and transcriptomic analysis to look for reliable, accessible and importantly high throughput biomarkers of mitochondrial dysfunction. This approach could then be used to define a subset of PD patients suitable for personalised intervention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Dynamic Neuromodulation
Funder: Medical Research Council

Abstract: I aim to utilize dynamic changes in neural synchrony to selectively modulate neural networks underlying oscillopathies such as essential tremor and Parkinson's disease. Specifically, 1) I will develop an on-line tracking system that a) determines the extent of cerebello-thalamo-cortical synchrony underlying essential tremor from peripheral measurements, and b) maps muscle activity to principal movement axis, in order to control the timing and pattern of stimulation delivered to thalamus according to the dynamic state of the tremor network. 2) Utilizing the fact that neural synchrony can be selectively enhanced or suppressed with phase specific deep brain stimulation, I will modulate transient synchrony between the medio pre-frontal cortex and subthalamic nucleus, implicated in decision making, in order to determine whether physiological transient synchrony is causally linked to behavior or epiphenomenal. 3) I will a) identify cortical lamina specific processes related to spontaneous suppression of pathological neural oscillations observed during Parkinson's disease, and b) replicate aspects of these interactions through stimulation in 6-OHDA-rat model of Parkinson's disease in order to establish the causal importance of lamina specific processes in termination of pathological neural oscillations and in motor impairment. 4) I will combine OPM-MEG and EMG in order to explore cortical dynamics impacting the severity of tremor. Detailed models of the thalamo-cortical circuit will be utilized in order to determine neural dynamics underlying tremor suppression during voluntary movement with the view to harness these dynamic changes to develop selective neuromodulation strategies in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: How CTIP2 deficiency drives medium spiny neuron degeneration and dysfunction: implications in Huntington's disease pathogenesis
Funder: Medical Research Council

Abstract: Dysfunction and neurodegeneration of striatal GABAergic medium spiny neurons (MSNs) is the core pathophysiological hallmark of Huntington's disease (HD). Increasing lines of evidence implicates impairments of MSN specification and maturation during development as major contributors to HD. Also, reduced CTIP2 transcription factor level and together with its dysfunction in the striatum are thought to contribute to HD pathogenesis. However, due to our limited knowledge of human striatal development and a lack of defined aetiology and causal mechanisms of pathogenesis, there is currently no effective treatment for this disorder. We have previously developed a reliable method for inducing MSNs from human embryonic stem cells (hESCs) and also generated CTIP2 mutant ESC lines using CRISPR technology. We found that CTIP2KO MSNs exhibited HD-like cellular pathologies compared to MSNs derived from isogenic control hESCs. Moreover, genome-wide RNAseq analysis of CTIP2KO MSNs revealed a significant overlap between CTIP2 regulated genes and those altered in HD iPSC-derived neurons and mouse models of HD, providing direct evidence that CTIP2-deficicy leads to MSN pathogenesis. Therefore, we will in this proposal determine how CTIP2 hypofunction leads to neuronal death and MSN dysfunction, and the extent of which contribute to HD pathogenesis, using a combination of CTIP2KO hESCs, HD iPSCs and animal models of HD. This work will determine gene regulatory networks and signalling pathways in striatal neurons governed by CTIP2 and provide insight into mechanisms behind cellular abnormalities in HD MSNs. The knowledge obtained from these studies will facilitate the development of new and more effective treatments for HD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL
Title: Studying the role of TDP-43 induced damage to the VAPB-PTPIP51 ER-mitochondria tethers in fronto-temporal dementia/amyotrophic lateral sclerosis
Funder: Medical Research Council

Abstract: Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are major neurodegenerative diseases that are known to be linked. Recently, we and others have investigated ER-mitochondria signaling in FTD/ALS. This is because many functions damaged in FTD/ALS are regulated by this signaling. These studies demonstrate that ER-mitochondria signaling is perturbed by a number of FTD/ALS associated insults. Notably, we have shown that TDP-43, a protein intimately linked to FTD/ALS disrupts ER-mitochondria signaling and that this involves breaking of the VAPB-PTPIP51 ER-mitochondria tethering proteins. The hypotheses to be tested in the project are that damage to the VAPB-PTPIP51 ER-mitochondria tethers is an early disease feature in TDP-43 linked FTD/ALS and that correcting this damage is protective in disease models. The Objectives are: 1. To determine the temporal sequence of ER-mitochondria signaling disruption in TDP-43 transgenic mice. This will reveal whether damage to ER-mitochondria signaling represents an early feature of disease. 2. To determine whether ER-mitochondria signaling is disrupted in neurons derived from induced pluripotent stem cells from FTD/ALS patients carrying pathogenic TDP-43 mutations. This will provide clinical relevance to the findings in the mouse models. 3. To determine whether correcting TDP-43 induced loosening of ER-mitochondria contacts via overexpression of VAPB or PTPIP51 is protective in cell models of FTD/ALS. This will provide evidence as to whether therapeutic targeting of damaged ER-mitochondria signaling might be beneficial. The studies will utilise transgenic models of FTD/ALS, iPS cell derived neurons and cell culture models including primary rodent neurons. The cell culture experimental approaches will include manipulation of expression of proteins by transfection and monitoring of phenotypes in all models by biochemical assays and advanced microscopy. All analyses will be performed blinded.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MICA: Sensory plasticity and adaptation in neurodegeneration
Funder: Medical Research Council

Abstract: The aim of this project is to understand the impact of neurodegeneration on sensory adaptation in the cerebral cortex. Neurodegenerative disorders have widespread impact on the cerebral cortex but the main target of research has been its impact on memory and cognition, processes that are poorly understood even in healthy humans and disease model organisms. Adaptation is an automatic form of sensory plasticity that relies on intrinsic cellular and synaptic mechanisms also thought important for learning and memory in other brain areas. Measurements of adaptation's effects therefore offer simple, direct measurements of plasticity in brain circuits, and a potential target for understanding, detecting and tracking neurodegeneration. Our hypothesis is that neurodegeneration has an early impact on sensory adaptation. We will test our hypothesis by measuring adaptation in the visual cortex of the rTg4510 mouse model of tauopathy, a group of neurodegenerative diseases including Alzheimer's disease. In preliminary experiments we find that adaptation is robustly affected in these mice even in early stages of degeneration. The proposed experiments will characterise the impact of degeneration on adaptation in visual and auditory cortex in this mouse model, and the temporal relationship between pathological and functional changes. We will gain knowledge of whether changes in adaptation are widespread, and whether these changes arise early in the degenerative process. The experiments will therefore tell us whether adaptation is a translational target for understanding, detecting and perhaps treating degeneration. These experiments will open up new directions for research, since the impact of degeneration on sensory plasticity has previously been largely ignored in both discovery research and clinical testing. Our experiments in mouse models of tauopathy will therefore push neuroscience research - and potentially, clinical practice - in new directions.


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