NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of alpha-synuclein in dopamine signalling in a highly physiological transgenic model of Parkinson's Disease
Funder: Parkinson's UK

Abstract: Physiologically-relevant animal models are of utmost importance for research into Parkinson's disease. Key findings from neuropathology, genetics and cell biology place alpha-synuclein at the centre of the molecular mechanisms of PD. However, current alpha-synuclein transgenic mouse models based on cDNA over-expression do not recapitulate the cardinal features of PD, specifically, the neurodegeneration of dopaminergic neurons in the nigro-striatal pathway and the formation of Lewy bodies. Taking a very different approach we have generated novel transgenic &quot;humanised&quot; mouse models which express either the A30P mutant or wild-type alpha-synuclein protein from a 135 kb human genomic SNCA locus to preserve correct spatial and temporal regulation of expression on a Snca-/- background. The SNCA-A30P transgene is expressed in the correct regions throughout the brain, including in tyrosine hydroxylase-positive neurons of the substantia nigra pars compacta. Pilot data suggest the mice exhibit a reduced release of striatal dopamine after evoked electrical stimulation. We will investigate in the mouse model the mechanisms by which alpha-synuclein affects dopamine homeostasis and neurodegeneration. We will characterise alpha-synuclein transgene expression throughout the brain, looking for emerging early-stage LB-like molecular pathology in aging mice. We will use fast-cyclic voltammetry on striatal slice preparations to further characterise dopamine release and reuptake and dissect the pharmacological mechanisms of synaptic regulation underlying reduced release. To understand the phenotypic effect of the cellullar and molecular changes we will perform a broad battery of sensitive behavioural tests capable of detecting neural circuit deficits in the absence of on overt phenotype in aging cohorts of mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding pathological spread in Parkinson's disease
Funder: Parkinson's UK

Abstract: The progressive nature of Parkinson's disease results in accumulation of disability and loss of non-motor functions associated with progressive accumulation of the disease-associated form of alpha-synuclein. The spread of alpha-synuclein pathology throughout the brain occurs in a relatively stereotyped, spatio-temporal manner. Although controversy surrounds the staging system proposed by Braak in Parkinson's disease, it is evident that neurodegeneration occurs in a non-random selective manner consistently affecting neighbouring brain regions. As a result of this pattern, it is possible to predict, in presymptomatic/early cases, regions that are likely to be affected in subsequent stages of Parkinson's disease, but do not yet exhibit the pathological hallmarks of the disease. By studying these pre-pathological brain regions, it may be possible to identify factors that determine how pathological propagation through the brain occurs, and also factors that underlie the selectivity of neuronal vulnerability in Parkinson's disease.This project aims to study the mechanism of pathological propagation of alpha-synuclein pathology in Parkinson's disease in post-mortem human brain. To this end, microdissection of Braak-predicted brain regions in controls, incidental Lewy Body disease cases (presymptomatic Parkinson's disease), and early Parkinson's disease cases will be performed. The tissue samples will be subject to biochemical analysis through a candidate target approach, and a proteomics based screening approach to identify alterations in protein expression between cases. This study aims to identify a molecular fingerprint that is common to affected neurons in Parkinson's disease and occurs prior to neuronal death, and that contributes to the mechanism of disease spread.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Does the loss of alpha-synuclein in the adult and ageing brain cause dysfunction of dopaminergic striatal synapses and contribute to progression of Parkinson’s disease?
Funder: Parkinson's UK

Abstract: Aggregation of alpha-synuclein is a hallmark of PD and believed to be one of the important triggers of dopaminergic neuron death in the SNpc. However, accumulation of aggregated alpha-synuclein in pathological inclusions within the neuronal cell bodies and axons could lead to gradually progressing depletion of the functional protein in neuronal synapses. Recent studies demonstrated that the normal physiological function of alpha-synuclein is important for the functional integrity of synapses, including dopaminergic synapses of SNpc neurons, and therefore it is feasible that alpha-synuclein loss-of-function contributes to nigrostriatal pathology in PD. Yet, in all models studied so far, complete knock-out of alpha-synuclein gene causes only limited changes in the nigrostriatal system. We hypothesise that because alpha-synuclein is important for normal synaptic function of nigral dopaminergic neurons, functional plasticity of these neurons during critical developmental periods ensures long-lasting compensation for complete loss of alpha-synuclein function caused by an inactivating mutation of the gene. In contrast, adult dopaminergic neurons lack such plasticity and develop synaptic dysfunction if depleted of alpha-synuclein. We propose a research programme to test this hypothesis. We will create an experimental model for inducible inactivation of the alpha-synuclein gene in adult and ageing mice and will study the consequences of this inactivation on survival of nigral dopaminergic neurons and function of their synapses. To the best of our knowledge, this will be the first attempt to surpass developmental plasticity and directly test whether the loss of alpha-synuclein in adult/ageing dopaminergic synapses is a factor contributing to the progression of PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mitochondrial function in LRRK2-related Parkinson's Disease
Funder: Parkinson's UK

Abstract: Background: The LRRK2G2019S mutation is the most common identifiable cause for Parkinson's Disease (PD). Mitochondrial dysfunction is of crucial importance in other forms of PD, but has not been systematically investigated yet in LRRK2G2019S mutant patient tissue. Pilot data: ATP levels were decreased and mitochondria elongated in LRRK2G2019S manifesting, but not in non-manifesting carriers. Our pilot data also suggest specific impairment of Complex IV in manifesting carriers. Overall aim: To characterize mitochondrial dysfunction, identify the underlying mechanisms and undertake rescue experiments in LRRK2G2019S mutant patient tissue. Specific objectives: 1. Detailed assessment of mitochondrial function and morphology in manifesting and non-manifesting LRRK2G2019S carriers. 2. Characterization of underlying mechanisms, namely: A) Determine effect of haploinsufficiency/LRRK2 knockdown on mitochondrial function; B) Investigate the role of 4E-BP; C) Assess the effect of LRRK2G2019S on mitophagy. 3. Rescue of mitochondrial function by A) Overexpressing parkin or B) Treatment with experimental neuroprotective agents. Methods: Objective 1: Standard biochemical and morphological analysis; Objective 2: A) siRNA knockdown of LRRK2 with subsequent biochemical/morphological analysis of mitochondria; B) Western blots to quantify phosphorylated/non-phosphorylated 4E-BP. Pharmacological inhibition of 4E-BP phosphorylation with Rapamycin; C) Western blots of parkin, PINK1, LC3 and p62, quantification of autophagic vacuoles and number of mitochondria encapsulated by LC3-positive autophagosomes, knockdown of LC3 to determine whether inhibition of mitophagy leads to rescue of mitochondrial impairment. Objective 3: A) Transfection with parkin constructs; B) Treatment with glutathione and its precursors. Expected outcome: Detailed characterization of mitochondrial dysfunction in LRRK2 disease may identify promising targets for future drug trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Zolpidem-sensitive beta frequency neocortical neuronal network oscillations in Parkinson’s disease; Diagnostic, biomarker and treatment.
Funder: Parkinson's UK

Abstract: Abnormal synchronous neuronal activity is a common phenomenon in pathological neurological conditions. Our recent brain imaging investigations have indicated exaggerated beta frequency (15-35Hz) oscillations in Parkinson's disease (PD) patients and that a sub-sedative dose of the hypnotic zolpidem is able to desynchronise these rhythms, the time course of which correlates with restored cognitive and motor function. We now wish to extend our studies in recently diagnosed (drug-free) PD patients in order to understand how specific cognitive and motor deficits relate to neuronal network activity and assess whether the desynchronising action of zolpidem is additive or synergistic with dopamine replacement therapy. Using pharmaco-magnetoencephalography we will record cortical oscillatory activity from unilaterally symptomatic PD patients, prior to initiation of dopamine replacement therapy. Fine motor movement and sensory stimulation will be used to locate the primary motor cortex (M1) and somatosensory cortex (S1). Oscillatory activity in specific frequency bands, in both unaffected and symptomatic M1 and S1 will be assessed in response to self-paced and directed motor tasks. These measures will be taken prior to and during administration of zolpidem and correlated with functional outcomes. PD patients will be recalled six months after initiation of dopamine replacement therapy and studies repeated in order to assess additive or synergistic effects of additional zolpidem administration. These results will provide the necessary rationale for the establishment of zolpidem as a viable alternative treatment in PD, and the use of pharmaco-MEG and zolpidem-sensitive beta oscillations as a biomarker for early diagnosis and monitoring of parkinsonian status.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Does Early Treatment of Parkinson's Disease Protect Motor System Plasticity and Connectivity?
Funder: Parkinson's UK

Abstract: Aim: To assess if early treatment of Parkinson's disease is associated with less impairment of motor system connectivity and response to plasticity protocols. Background: Both the TEMPO and ELLDOPA trials suggest that earlier treatment of Parkinson's disease leads to less disability 6-12 months later, even when any symptomatic effects of the drugs are taken into account. Here, we hypothesie that this is due to the beneficial effect of dopaminergic drugs on brain plasticity processes, which help to prevent maladaptive changes in the motor system. Methods: We will recruit 15 previously untreated patients with early Parkinson's disease who have decided with their treating doctor to start on treatment and 15 patients with a similar level of disability and disease duration who have instead decided to delay treatment for 3-6 months. We will assess at baseline, prior to treatment commencement and 6 months after treatment commencement: response to paired associative stimulation, pre-motor/motor interactions, cortical excitability and clinical symptom rating. Predicitions: That the rate of change in electrophysiological and clinical ratings will be slower in those who decided to introduce medication earlier.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Can we safely treat and monitor people with Parkinson's disease in Tanzania: a model for sub-Saharan Africa?
Funder: Parkinson's UK

Abstract: Through a door-to-door, community-based prevalence study in Hai, Tanzania, 33 patients with Parkinson's disease (PD) were identified from a population of 161,000 people. This is the largest prevalence study of PD in sub-Saharan Africa (SSA). The majority were previously undiagnosed and untreated, despite some having symptoms for many years. Drug treatment in late stage PD can lead to a number of side effects and complications. Little is known about the effect of introducing therapy to drug-na&iuml;ve patients at this stage. All surviving patients (16) have received treatment for 3 years and we propose to follow them for another 3 years to titrate doses, and document and manage emerging side effects. This study would not be possible in the UK or other developed countries, as patients begin treatment at, or shortly after, diagnosis. However, we believe that many similar patients exist in developing countries for whom the care model developed may be appropriate. The study will provide information on treatment in such patients and insight into the mechanism of motor complication development and the differing contributions of disease and treatment duration. We will report on the feasibility, safety, adherence and efficacy of treating patients in a developing country, and the impact on quality of life and health beliefs. The surviving patients will be reviewed monthly by the UK-trained Tanzanian PD nurse specialist and at least yearly by UK research doctors who will be also be available for phone and email advice. Response to treatment and any side effects will be recorded.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Testing the prion hypothesis of Parkinson's disease
Funder: Parkinson's UK

Abstract: This proposal will test the hypothesis that Parkinson's disease (PD) has a prodromal phase in which alpha-synuclein precipitates intracellular disease that starts in the neuroenteric axis, and then spreads from cell to cell throughout the brain in an anatomically defined, stochastic, prion like fashion, and that targeting this pathogenic cascade could significantly slow down or stop PD. Our specific aims are 1) to set up an in vitro cellular system where spreading of alpha-synuclein from neuron to neuron can be studied to determine whether transmission occurs through synapses; 2) to show that the accumulation of alpha-synuclein targeted to the gut leads to spread of pathology through the CNS; 3) to show in vivo that this spread of alpha-synuclein occurs by the transmission of pathological proteins in a prion like fashion, and that this process is dependent on the species of alpha-synuclein and the type and level of alpha-synuclein in the infected cell.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Developmental Clinical Studies - new use of a licensed drug in preventing autoimmunity after alemtuzumab treatment of MS
Funder: Medical Research Council

Abstract: We propose to test the efficacy of a licensed drug to prevent autoimmunity caused by reconstitution following lymphocyte depletion. The specific context of this trial is autoimmunity after alemtuzumab (formerly ?Campath-1H?) treatment of multiple sclerosis, but positive results would have implications for many clinical contexts. Alemtuzumab is arguably the most effective treatment of multiple sclerosis to date; if autoimmunity, its most significant adverse effect, could be minimised then many more people would benefit from this efficacy. Multiple sclerosis is the most common cause of disability in young adults in the Western world, effecting 100,000 people in the United Kingdom. Treatments to date have been only partially effective. Alemtuzumab is a lymphocyte-depleting humanised anti-CD52 monoclonal antibody, investigated by us as a treatment of multiple sclerosis since 1991; it is a rare example of academic-led translational medicine. Our phase 2 results of treatment of early relapsing-remitting multiple sclerosis demonstrate greater efficacy of alemtuzumab, compared to standard licensed therapy (interferon-beta1a), than any other treatment of multiple sclerosis. An unprecedented result was that that disability of patients five years after alemtuzumab was improved from baseline. Phase 3 trials of alemtuzumab will complete by Q42011 and submissions for licensing will be in Q32012. T-cell reconstitution after alemtuzumab occurs by expansion of peripheral T-cells that have escaped depletion, rather than by the generation of new T-cells via the thymus. This results in a population of T-cells that are restricted in diversity and skewed towards auto-reactivity. It is likely that these cells cause the main adverse effect of alemtuzumab, namely autoimmunity months to years after treatment (30% of patients develop thyroid autoimmunity and 3% idiopathic thrombocytopenic purpura); this risk is increased in patients with high serum IL-21. The hypothesis underlying this trial is that autoimmunity after alemtuzumab will be reduced if this peripheral T-cell expansion is suppressed by increasing thymic production of naive T-cells. Our investigational drug has these effects in a variety of animal models. It is licensed for use in humans (for a different indication) and is well tolerated. To date no-one has investigated its effect on thymic reconstitution in humans. So, we propose a double-blind randomised (1:1) placebo-controlled trial of our investigational agent in 42 patients treated with alemtuzumab for relapsing remitting multiple sclerosis who are at high-risk of developing. The primary outcome measure will be the development of secondary autoimmunity following treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Overcoming mechanical barriers to neuronal regeneration
Funder: Medical Research Council

Abstract: Neuronal regeneration in the mammalian CNS is very limited. After nerve tissue injury a glial scar is formed across which axons cannot grow. Intensive research studying biochemical signalling by the inhibitory scar tissue revealed several factors detrimental to neuronal regeneration. Despite this increasing knowledge, CNS tissue repair can currently not be promoted, indicating that other factors contribute to the failing neuronal regeneration. It has been suggested that the (potentially stiff) glial scar poses a mechanical barrier for neurons. However, the mechanical properties of glial scars were never measured, and the neuronal ability to respond to mechanical cues is currently poorly understood. Furthermore, neural implants, which are significantly stiffer than healthy nerve tissue, cause foreign body reactions, limiting their lifetime. This proposal will illuminate the effect of mechanical signalling on these CNS pathologies. In contrast to mammals, in lower vertebrates regeneration in the CNS is often successful. To investigate if mechanical cues contribute to this different regenerative ability, I will develop an atomic force microscopy technique and, for the first time, measure the mechanical properties of glial scars in rats and frogs. I will correlate differences in stiffness with the tissues‘ histological structures. After injury, glial cells undergo reactive gliosis, which leads to scar formation and foreign body reactions. The initial gliosis inducer is still unknown. I will culture glial cells on custom-built substrates of varying compliance and investigate their gene and protein expression, thus testing whether mechanical cues trigger gliosis in vitro. I will also study how mechanical stimuli impact neurons by quantifying their outgrowth on compliant substrates. Ultimately, I will implant materials of different stiffness into rat CNS tissue and test if in vivo gliosis can be triggered exclusively by mechanical cues. Finally, I will investigate molecular mechanisms of the transduction of mechanical cues into intracellular biochemical signaling. I will identify channel proteins likely involved in CNS cell mechanosensitivity, pharmacologically and genetically interfere with the channel proteins found in vitro and in vivo, and thus explore the role of specific mechanosensitive ion channels in CNS pathology. Understanding CNS cell mechanosensitivity may eventually lead to novel, groundbreaking treatment strategies of CNS lesions such as spinal cord injuries. Pharmacological intervention with cellular mechanotransduction pathways or the implementation of proper mechanical cues in the damaged tissue could - in addition to appropriate biochemical stimuli - promote axonal re-growth and suppress reactive gliosis, which ultimately will result in neuronal regeneration and functional recovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: New insights into pain mechanisms
Funder: Medical Research Council

Abstract: At any one time 6% of the population is in severe pain. Despite this huge clinical burden, our understanding of the cellular mechanisms involved in pain processing is limited and the treatments available are often only partially effective. I study rare families in which pain insensitivity or paroxysmal pain are caused by a mutation in a single gene in order to gain powerful insights into pain mechanisms and to give a route to new therapies. This is exemplified by my previous work showing that Channelopathy-associated Insensitivity to Pain (CIP) is caused by loss of function of Nav1.7, a nociceptor-expressed voltage-gated sodium channel; and by Familial Episodic Pain Syndrome which was shown to be caused by an activating mutation in TRPA1, the chemosensitive transient receptor potential channel. This proposal aims to further characterize the function of Nav1.7 through the analysis of two C-terminal CIP mutations and find other crucial genes involved in human pain sensing which I will then extensively study by generating and analysing mouse mutants. Through collaborations with European-based pain clinicians I have access to a rich cohort of patients with Mendelian pain disorders in which known disease genes have been excluded. This cohort includes (1) a three generation family with 6 affected individuals with pain insensitivity that segregates autosomal dominantly; (2) three consanguineous families with pain insensitivity due to congenital or progressive neuropathies; (3) four singletons with complete absence of pain sensation but with peripheral nerves intact; (4) a collection of patients with paroxysmal pain disorders (including paroxysmal pain and congenital erythermalgia); (5) a mother and daughter with extreme cold allodynia; and (6) three individuals who cannot sense cold pain. The strategy which will be adopted to find each disease gene will involve the use of whole exome sequencing, which is already being performed in a collaborating laboratory for a subset of this cohort. Once the disease genes are proven I will prioritise two of the most interesting for transgenic mouse creation and characterize the pain phenotype using appropriate behavioural, anatomical and electrophysiological assays. The mouse mutant analysis will capitalize on expertise in the Wood lab who routinely use the Cre-Lox P approach to conditionally knock out genes. By identifying and functionally characterizing novel pain genes this proposal has the real potential to lead to a better understanding of pain production and could lead to the development of better analgesics which will benefit us all.


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