Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) are rare neuromuscular diseases lacking diagnostic biomarkers. During the last decade, our teams have demonstrated that cell adhesion molecules (CAMs) play a crucial role in the formation of the nodes of Ranvier. Particularly, the complex Contactin-1/Caspr-1/Neurofascin controls paranode formation and the electrical insulation of the myelin. We found that antibodies to CAMs are detected in Guillain-Barré syndrome, and mediate demyelination. By contrast, autoantibodies in CIDP and MMN are only present in a small subgroup of patients. We recently demonstrated that a subgroup of CIDP patients show autoantibodies to Contactin-1 and Caspr-1. Of interest, this specific reaction could orientate their treatment. Here, we combined our efforts to elucidate how immune attack at nodes participates in CIDP severity and to test novel therapy. We propose to: Aim 1: Screen the reactivity to nodal antigens with the clinical features of CIDP and MMN patients. Aim 2: Identify new nodal and paranodal antigens using proteomic approaches: mass spectrometry and mammalian expression bank. Aim 3: Generate animal models of CIDP to study the pathological processes of CIDP. Aim 4: Use in vitro models (myelinating co-culture) to monitor the pathogenic effects of autoantibodies. Altogether, these results will advance tremendously the knowledge on the pathophysiology of CIDP and will help defining prognostic subgroups and guide novel therapeutic approaches.
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Neuroinflammation is how the immune system of the brain fights against diseases. As a natural defense mechanism, this reaction may harbor beneficial effects, but under circumstances not yet well understood, it may also have detrimental consequences for the brain and even contribute to the progression of the disease that initially stimulated the immune reaction. The present proposal will study the mechanisms by which neuroinflammation could transition from a beneficial to a detrimental outcome in preclinical models of Alzheimer’s disease (the most prevalent form of dementia), amyotrophic lateral sclerosis (the most common motor neuron disease), and septic encephalopathy (the leading cause of mortality in intensive care units), three diseases sharing a prominent inflammatory component. Moreover, it will aim to identify genetic factors marking the key steps of this transition, both in preclinical models and samples of patients suffering from the respective diseases, in order to find points of intervention for early diagnosis and development of better targeted and more efficient therapeutic strategies.
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This study will evaluate the needs and provision of care for patients in the late stages of Parkinsonism and their carers in several European countries. This will done through an in-depth assessment of patients and carers, interrogation of national and regional databases, and assessment and outcome of management strategies in six European countries. We will compare the effectiveness and cost of different health and social care systems, and carry out a trial comparing assessment by a specialist with management suggestions, guidance and access to telephone advice to that of usual care. A systematic literature review of the evidence for effective management strategies, analysis of the study data, and evaluation of change in outcomes following specialist review will provide the basis for recommendations in the management of late stage Parkinsonism. In addition, the project will produce a platform for the assessment of patients with late stage Parkinsonism, their current treatment and care provision, as well as guidelines on the management of this late disease phase. The results may also provide a model for the research on better management of other chronic neurological disorders and age-related disorders in various health-care systems.
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Despite the advances in the identification of genes involved in Parkinson’s disease (PD), there are still appreciable gaps in our understanding of the mechanisms underlying the neurodegenerative process and its relation to environmental factors in PD. Therefore we are proposing a comprehensive approach based on (i) a unique collection of families with autosomal dominant and autosomal recessive PD and (ii) large cohorts of clinically well-defined sporadic PD patients from different populations worldwide for (iii) genetic studies and (iv) assessment of environmental modifiers that will translate into (v) functional validation studies in patient-derived cellular models. Using next generation sequencing strategies including exome sequencing in multiplex families and targeted resequencing in sporadic PD patients, we will disentangle the complex genetic architecture of PD in different populations and attempt to better define the underlying functional variants in disease-associated GWAS loci. Newly identified genetic variants are filtered for pathogenic relevance based on novel prediction algorithms combined with unique expression databases and replicated in large cohorts of PD patients. Here the Genetic Epidemiology of Parkinson’s disease Consortium (GEO-PD) provides a unique resource with a large number of DNA samples and environmental exposure data of PD patients and controls from different populations worldwide. Subsequent assessment of disease modifiers includes two complementary approaches: Mendelian randomization, and gene-environment interaction studies. In order to validate genetic risk variants, functional studies on patient-based material will be performed. Here the applicants provide unique expertise for fibroblasts- and induced-pluripotent-stem-cells-(iPSC)-derived cellular models of PD and a large repository of biomaterials from carriers of PD-associated mutations. Established readouts allow to study functional effects of identified genetic risk factors and will be used to assign novel disease genes and risk variants to defined pathogenic pathways. Moreover patient-based cellular models will be challenged with environmental risk factors identified as modulators of disease. We expect that the combination of comprehensive state-of-the-art genetic technologies with a detailed ascertainment of environmental modifiers will provide important clues to decipher the complexity of neurodegeneration in PD. Subsequent modelling of PD in patient-based material allows to discover molecular mechanisms and pathways involved and leading to therapies for this still incurable disease.
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ALS is a devastating neurological disease causing progressive and relentless paralysis over months to years until death from respiratory failure. ALS kills 1 in every 300 people and is the commonest reason to seek assisted suicide. The aim of the STRENGTH consortium is to identify factors that affect susceptibility to ALS or modify the pattern of ALS onset or survival duration as targets for the development of new therapies. Until now, the usual approach has been to consider ALS as a homogeneous disease and identify genetic or environmental risk factors. STRENGTH uses a novel approach, first using clinical, laboratory and sophisticated clustering methods to identify homogeneous patient subgroups to increase power, and second using multiple layers of data from environmental questionnaires and genetics from the same individuals enrolled in pan-European population registers covering a population of about 120 million people, to identify for the first time how risk and protective factors work in concert to cause and modify ALS. In addition, STRENGTH partners include epigeneticists, able to develop this field in ALS and to further reveal the interface between genetic and environmental interaction. STRENGTH capitalises on existing infrastructure from the EU funded EuroMOTOR project which enables collection of large data sets, and the JPND funded SOPHIA project which ensures the data collection follows standard operating procedures throughout Europe, and will enable the discovery of new pharmaceutical targets for ALS.
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