Partners
Partner 1: Olaf RIESS, Saskia BISKUP, Department of Medical Genetics, University of Tuebingen, Germany
Olaf Riess is the head of the department of Medical Genetics in Tuebingen, Germany, one of the largest departments of Medical Genetics in Germany. Currently Olaf Riess is coordinating a large research programme named RATstream that is funded by the European commission. His group has longstanding experience with generation, high-throughput characterization and preclinical treatment studies in rat models of different neurodegenerative diseases. Within this project we aim to generate a new rat model for Parkinson’s disease. The above mentioned expertise of Olaf Riess will be fundamental for the successful outcome of the herein proposed project.
As part of a common world spanning effort, Saskia Biskup identified mutations within the gene LRRK2, now recognized as an important cause for sporadic and familial Parkinson’s disease worldwide. She went on to characterize expression and localization patterns of LRRK2 in mammals with special emphasis on LRRK2 mouse models. She was also involved in the discovery that mutations within LRRK2 lead to increased kinase activity in vitro. Saskia Biskup’s expertise will be of great importance for the generation of the LRRK2 transgenic rat model, the characterization of LRRK2 related functions in order to deliver parameter sets for pre-clinical trials in the rat.
Group’s participants:
- Prof. Olaf Riess - Dr. Dr. Saskia Biskup
- PD Dr. Thomas Ott - Post-doctoral fellow (to be hired)
- Dr. Natalja Funk
Tasks in the project
SP1, WP7: Generation and characterisation of a LRRK2 transgenic rat model
Partner 1: Philipp KAHLE, Hertie Institute for Clinical Brain Research, Tübingen, Germany
Prof. Kahle (Laboratory of Functional Neurogenetics, Department of Neurodegeneration) is a biochemist specialized molecular and cellular biology and animal models of neurodegenerative diseases, mostly PD. Using state-of-the-art biochemical/enzyme assays, molecular biology techniques (cloning, site-directed mutagenesis, cell biology and advanced imaging methods, C. elegans and mouse models, this group has made significant contributions to the understanding of the molecular mechanisms of neurodegenerative proteopathies. Specifically for this project, cellular pathways how parkin protects against neurodegeneration caused by protein misfolding and oxidative stress were elucidated in C. elegans and novel cell culture systems.
Group’s participants:
- Prof. Philipp Kahle, PI 1
- Dr. Wolfdieter Springer, group leader C. elegans, project head parkin
- Sven Geisler, PhD student (biological chemist)
- Angela Treis, diploma student (biologist) - Elena Cornejo-Castro, student employee (biologist)
- Diana Skujat, technician (BTA)
Tasks in the project
- SP2: Coordination and performance of WP1 regulation of parkin ubiquitin ligase activities and substrate selection
Partner 1: Thomas GASSER, Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany
The group of Prof Gasser has a long-standing interest in the genetics of Parkinson’s disease and other movement disorders. Major contributions to the field were the identification of the LRRK2 gene as the most common cause for autosomal-dominant parkinsonism (Zimprich et al., 2004), and the delineation of the clinical spectrum of LRRK2-associated PD (Berg et al, 2005). The group has also contributed to the characterization of parkin-associated early-onset parkinsonism (Lücking et al., 2000) and has identified and characterized a family with a duplication and a triplication of the a-synuclein gene in different branches of the family (Fuchs et al., 2007). Another focus of the group is the study of imaging markers in PD, particularly the echongenicity of the substantia nigra (Gaenslen et al., 2008).
The group is running the largest PD out-patient unit in Southern Germany and has established a large DNA-bank. We are also following a large number of patients with genetically defined PD, as well as presymptomatic mutation carriers, and have established a biobank of DNA, CSF, blood and fibroblasts from patients with genetically defined PD.
Group’s participants
- Prof. Dr Thomas Gasser, PI - Prof. Dr Daniela Berg, coPI
- Clinical associate Dr. Kathrin Brockmann, M.D
- Post-doctoral fellow (to be hired) - PhD student (to be hired)
- Dr. Holm Graessner, Research manager (Department of Medcial Genetics)
Tasks in the project
- Overall co-ordination of the project
SP3: co-ordination of WP1 MEFOPA-Registry and WP2 Biobank
Partner 1: Michael Bonin; Peter Bauer, Olaf Riess, Institute of Human Genetics, Department of Medical Genetics, Uni Tuebingen
Part of the Department of Medical Genetics is the Microarray Facility Tübingen that is headed by Dr. Michael Bonin. Michael Bonin (Dept. of Medical Genetics) is a Molecular Biologist with a focus on transcriptional processes in neurodegenerative diseases, including characterization of animal models for Parkinson’s disease. His research focuses on the role of mRNA and miRNA in disease mechanisms using microarrays as a core technology. He is head of the Microarray Facility Tübingen as a core facility for all Affymetrix and Illumina microarray applications. The facility is Affymetrix and Illumina Service Provider for expression and SNP analysis. Technically, it is equipped with the most recent scanner system and with the appropriate technology. Together with the collaborators at the Universities of Harvard (Prof. Krainc), Luebeck (Prof. Klein), Ljubljana (Prof. Peterlin, Lovrecic, PhD student) we developed the “haemogenomic“ approaches through the study of blood biomarkers for neurodegenerative disorders such as HD, PD, and SCA. Furthermore, the department has just recently began to offer service in a Next-Generation Sequencing core facility that is headed by Dr Peter Bauer. Dr. Bauer is also head of diagnostical section of the department.
Group’s participants
Prof. Dr. Olaf Riess (supervision/management)
Dr. Michael Bonin (head of microarray facility)
Dr. Peter Bauer (head of Diagnostics and NGS)
Dr. Michael Walter (Microarray Facility Data analysis, Bioinformatics)
Tasks in the project
- SP3, WP3: Investigation of transcpritional changes in ex vivo cells from patients with rare Mendelian forms of Parkinson’s Disease: whole genome transcriptome analysis in whole blood samples and second generation sequencing will be performed using a GS FLX genomic sequence
Partner 2: Leonidas STEFANIS, Kostas VEKRELLIS, Biomedical Research Foundation, Academy of Athens
Many neurodegenerative diseases, including Parkinson’s Disease (PD), are characterized by the accumulation of oligomeric protein species and extra- and intra-cellular fibrillar aggregates, harboring beta sheet-rich secondary structures. Such aberrant conformations appear to be deleterious to neurons, but exactly which species are involved is unclear. The groups of Drs. Vekrellis and Stefanis at BRFAA are focusing their investigation on alpha-synuclein (AS), a molecule genetically, biochemically and pathologically linked to PD. We are studying the regulation of AS levels in neuronal cells, as well as the regulation of particular AS species. Furthermore, we are studying the pathogenic effects of such species in various neuronal cell models and in vivo. We are focusing particularly on potential deleterious effects on the cell proteolytic machinery and we are independently studying proteolytic dysfunction as a potential unifying theme in neurodegenerative conditions. In the process of this work, we have developed a number of inducible neuronal cell culture systems of expression of various forms of AS. These cells are used as a model of protein aggregation and neurodegeneration. Such studies are extended to primary neuronal cell culture systems, which are routinely performed in the lab, and in vivo transgenic mouse models. We are also studying in the effects of variants of other genes associated with PD, such as UCH-L1 and Parkin. Furthermore, we are studying specific naturally occurring forms of AS that are secreted from cells.
Group’s participants:
- coPIs Leonidas Stefanis, Kostas Vekrellis -Post-doctoral fellow Evangelia Emmanouilidou
- PhD student Katerina Melachrinou
-Collaborators: K. Karalis (BRFAA), O. Riess (Tubingen), K. Gerozzisis (CNRS, Paris)
Tasks in the project
- Vice – coordinator of the consortium
SP1 : coordiantion and perfomance WP2: Pathophysiology of secreted alpha-synuclein species
Partner 3: Deniz KIRIK, Lund University, Sweden
Prof. Kirik holds an MD and has a PhD in neuroscience. His research during the last 12 years has focused on development of new animal models and novel cell and gene-based therapeutic strategies for neurodegenerative diseases. More recently he became interested in metabolic and functional imaging at the systems level to elucidate dysfunction in the diseased living brain and mechanisms of repair using MR imaging and spectroscopy and high resolution PET. Kirik is the author/co-author of more than 75 peer-reviewed scientific papers. He has participated 6 major EC projects within the 6th and 2 projects in the 7th framework programs. He is the co-director of the Experimental Bio-Imaging center at Lund University, Section editor in Experimental Neurology, and contributing editor in European Journal of Neuroscience. He is been the President of the Network of European CNS Transplantation and Restoration during 2006-2008.
Group’s participants:
Deniz Kirik MD, PhD Scientific project coordination
Gurdal Sahin, MD Functional assessments
Ayse Ulusoy, Msc In vivo gene transfer
Björn Anzelius, MSc AAV vector production
Anneli Joseffson Animal tech
Ulrika Sparrhult.-Björk Histology tech
Tasks in the project
- SP1: coordination and performance WP4: Role of oxidative stress and microglial response in alpha-synuclein-mediated nigral neurodegeneration
Partner 3 Christer NILSSON, Department of Clinical Sciences, Section of Geriatric Psychiatry, Lund University.
Dr Nilsson is a clinical neurologist with a background in neurobiology. Dr. Nilsson directs a large clinical center for neurodegenerative diseases, including PD and related movement disorders in Sweden. He has expertise in atypical parkinsonian disorders and dementia, and has participated in several multicenter studies on MSA, within the framework of the European MSA Study Group. Dr Nilsson and Dr Puschmann study families with hereditary PD in southern Sweden, with the aim to characterize the phenotype, genotype and biological parameters in each family. Drs. Nilsson, Farrer and Gasser recently discovered the basis of inherited parkinsonism in a large Swedish kindred, the Lister family complex, initially described by Lundborg, 1913 and Mjönes in 1949. Multiple branches of this family, which now exceeds a genealogy of 2,500 individuals, carry duplications and triplications of the SNCA locus, respectively. In addition, 40 families with autosomal dominant inheritance but without known mutations have been described.
Group’s participants
- Dr Christer Nilsson, MD, PhD (PI)
- Dr Andreas Puschmann, MD (PhD student)
- Dr Samuel Gebre-Mehdin, MD, PhD; Consultant neurogeneticist
- Jan Reimer, Research Nurse
Tasks in the project
- SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 4: Poul Henning JENSEN, University of Aarhus (UA), Denmark
The Neurodegenerative research group at UA has a strong background on the molecular, cellular and pathological function of a-synuclein (AS), which is a key player in Parkinson's disease (PD). Previously, we identified protein partners for monomeric and aggregated AS by biochemical and proteomic tools (Jensen 1999; Lindersson 2004). Based on these studied we have focussed on proteins that has the potential to stimulate AS aggregation in order to develop cellular models that truly display intracellular AS aggregate dependent cytotoxicity (Lindersson 2005). In this project we will in collaboration with others groups in the consortium exploit this model to investigate the relation between AS and LRRK-2, another important genetic PD player, modifiers of AS post translational modifications and the stress of secreted AS. We will also study the early cellular response to the development of intracellular AS aggregates by gene expression analyses and in collaborations validate these responses in other cellular and animal models of PD with the aim of identifying novel biomarkers. Such validated responses will likely point to novel therapeutic targets in PD related signalling cascades.
Group’s participants.
- Dr Poul Henning Jensen PI
- Louise Buur Lund PhD student
- Cristine Olesen PhD student
- Post-doctoral fellow (to be hired)
- Jette B. Lauridsen Technician
Tasks in the project
- SP1: coordination and performance of WP1: Effects of oligomeric alpha-synuclein on cellular homeostasis
Partner 5: Tiago OUTEIRO, Instituto de Medicina Molecular (IMM) Lisbon, Portugal
The Cell and Molecular Neuroscience Unit at the IMM has a strong background on the molecular basis of neurodegenerative disorders associated with protein misfolding, such as Parkinson’s disease (PD). Previously, we established yeast models of PD by the heterologous expression of a-synuclein (Outeiro and Lindquist, 2003). We have also developed a novel system to study the initial steps of a-synuclein oligomerization which will enable us to search for modifiers of cytotoxicity and fibrillation (Outeiro et al., PLoS One, 2008). In this project we will exploit powerful genetic screens to identify novel modifiers of a-synuclein post-translational modifications. We will also investigate the role of Parkin and LRRK2 on a-synuclein modifications and aggregation, in collaboration with the other groups in the consortium. A better understanding of the molecular mechanisms involved in these processes might lead to the identification of novel biomarkers or novel targets for therapeutic intervention. Ultimately, we will also want to image a-synuclein in vivo, using two-photon microscopy, in mouse models of PD. This final task will enable us to test in vivo the effect of the candidates we identify as modifiers of post-translational modifications on a-synuclein aggregation in the brain, and will provide further validation of the putative targets/biomarkers.
Group’s participants:
- Dr. Tiago Outeiro PI
- Dr. Teresa Pais Senior researcher
- Post-doctoral fellow (to be hired)
- Oldriska Marques PhD student
Tasks in the project:
- SP1: coordination and performance of WP3: Identification of factors that influence alpha-synuclein oligomerization in cell culture and in vivo
Partner 6: David RUBINSZTEIN, University of Cambridge, UK
Professor Rubinsztein’s laboratory is based in the Cambridge Institute for Medical Research (CIMR). CIMR is a thriving cross-departmental institution within the Faculty of Clinical Medicine at the University of Cambridge comprising approximately 250 scientists, a quarter of whom are graduate students. Access to the following core technologies is available to all groups: microscopy (fluorescence, confocal and live cell), fluorescence activated cell sorting and bioinformatics. The Rubinsztein lab has the necessary equipment and expertise to support this project. The Department of Medical Genetics, in which Professor Rubinsztein is based in the CIMR includes 5 Professors and 3 Readers within its academic staff. As a member of the Clinical Laboratory Sciences it received a 5* (highest possible) rating in the most recent UK Research Assessment exercise.
Skill and Experience
David Rubinsztein is Professor of Molecular Neurogenetics at Cambridge University, a Wellcome Trust Senior Clinical Research Fellow and an Honorary Consultant in Medical Genetics at Addenbrookes Hospital. The Rubinsztein group currently comprises10 postdoctoral scientists, 5 PhD students and 1 technician. In addition to a major focus on cell biology of diseases caused by intracellular aggregate-prone proteins, like Huntington’s disease and Parkinson’s disease, they have made major contributions to the understanding of autophagy in the contex of neurodegeneration, and have extensive expertise in mouse modelling and therapeutics, and Drosophilla genetics (in collaboration with Dr Cahir O’Kane). Over the last 3 years, the group have published 57 papers, including journals like Nature Chemical Biology (2 papers), and Nature Neuroscience, and reviews in Nature and Nature Reviews in Drug Discovery.
Group’s participants. (example)
- Pro David Rubinsztein, PI
- Post-doctoral fellow to be hired
- Maike Lichetenberg, PhD student
Tasks in the project
- SP1: coordination and performance of WP6: Beyond kinase activity: Examination of other factors influencing LRRK2 neurotoxicity
Partner 7: Giorgio Rovelli, Novartis Pharma AG, Switzerland
12-year expertise in establishing biochemical and cell-based assays to be used for high-throughput screens for small molecular weight compounds. Those screens are aimed at identifying lead compounds that penetrate the brain and antagonize neurodegenerative mechanisms in vivo. Main task is the biochemical characterization of neuronal proteins that carry autosomal dominant mutations (presenilins, LRRK2 etc.) and their validation as molecular targets for drug discovery projects. Mrs Barske, Dr. Kaupmann and I independently lead molecular and cellular laboratories that belong to the Neuroscience department at NIBR (Novartis Institutes for BioMedical Research), which has a mission to discover and develop treatments that improve the lives of patients with neurodegenerative or psychiatric diseases. For neurodegeneration, our focus is find disease-modifying treatments by ameliorating the toxic effects of protein misfolding, the shared mechanism underlying disorders like Huntington's, Parkinson's or Alzheimer's disease. Dr. Shymshek leads an in vivo laboratory, he is responsible for the generation and characterization of LRRK2 mouse models.
Group’s participants.
- Dr Giorgio Rovelli PI - Dr. Klemens Kaupmann coPI
- Post-doctoral fellow (to be hired) - Dr. Derya Shimshek
- Carmen Barske
Tasks in the project
SP1: coordination and performance of WP5: Examination of the role of LRRK2 in cellular pathways: focus on the kinase activity
Partner 8: Olga CORTI, U 679, INSERM, France
The group of Dr Corti is focused on the understanding of the physiopathological functions of Parkin and its potential interactions with other Parkinson’s disease-related proteins. Our most recent, as yet unpublished studies, have led to the identification of a new putative mitochondrial Parkin substrate. Evidence in Parkin deficient mice and in cell models suggests that Parkin modulates the association of this protein with the mitochondrion. In this project, we shall characterize the molecular interactions between Parkin and its novel mitochondrial substrate, and their functional consequences. Particularly, we will explore the mechanisms by which Parkin modulates the mitochondrial localization of this protein, and determine how this regulation affects mitochondrial function, shape and dynamics. In collaboration with other partners of the consortium (Whitworth, Kahle), we shall investigate the potential interactions between Parkin and other candidate components of the PINK1/Parkin pathway, and analyze the contribution of new co-enzymes to the mitochondrial functions of Parkin. We will also contribute to the validation of small molecule compounds of therapeutic potential (Trophos). Finally, animal models will be shared with other partners for collaborative purposes.
Group’s participants.
- Dr Olga Corti, PI - Pr Alexis Brice, coPI
- Dr Lori Buhlman, Post-doctoral fellow
- Assistant Engineer, to be hired - Giulia Bertolin, M2/PhD student
Tasks in the project
SP2: coordination and performance of WP2: Dissecting the molecular mechanisms involved in the Parkin-dependent modulation of mitochondrial functions
Partner 8: Alexis BRICE, INSERM, France
This research group focuses on the clinical and genetic characterization of patients with different neurodegenerative and movement disorders, including Huntington’s disease, PD, cerebellar ataxias and dystonia. Dr Dürr and Prof Brice coordinate several national and international networks for research in PD (Parkinson’s Disease Genetics in France), inherited ataxias and spastic paraplegias (SPATAX network, clinico-genetic coordination of EUROSCA) and HD (French network of centers for presymptomatic testing in neurological disorders). Prof Brice coordinates a national reference center for neurogenetics at the Pitié-Salpêtrière Hospital. Prof Brice and Dr Dürr have established a national network of 14 movement disorders centers that participate to the so-called PDG (Parkinson’s Disease Genetics) network. This network has started in 1992 and has collected more than 500 families with Parkinson’s disease using very stringent clinical diagnostic criteria. There are already more than 200 patients or carriers of mutations in genes involved in PD. The group has produced more than 300 publications in international journals. Major financial support is provided by the Agence Nationale pour la Recherche, the European Commission and the National Institutes of Health (NIH).
Patients will be recruited through the PDG network which has already identified a large number of patients with disease-causing mutations and will continue to recruit new patients. They will be included in the study at the Pitié-Salpêtrière Hospital in Paris by members of our team experts in clinical research.
Group’s participants
- Pr Alexis Brice, PI - Dr Alexandra Dürr
- Dr André Troiano, Neurologist - Dr. Céline Jauffret, clinical research assistant
- Dr. Cécile Zaros, clinical research assistant
- Florie Fauché, technician
Tasks in the project
SP3: This group will be responsible for recruitment, clinical evaluation and genetic testing of patients with mutations in the major PD-associated genes, SNCA, LRRK2, parkin, PINK1 and DJ1, and appropriate control subjects. It will contribute to the generation of the data and biomaterial bank, foreseen in the study, through collection of biological samples.
Partner 9: Veerle BAEKELANDT, Katholieke Universiteit Leuven, Belgium
Prof. Baekelandt (Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine) is a Neuroscientist specialized in Parkinson’s disease. Her research focuses on the development of animal models and gene therapy for Parkinson’s disease using viral vectors as core technology. Viral vector-mediated local over-expression or inhibition of disease-associated genes in the brain of laboratory animals is an efficient approach for basic research into the pathogenesis of neurodegeneration, for the development of (gene) therapeutics and diagnostics and for functional genomics. Expertise of the group consists of stereotactic neurosurgery and optimization of in vivo gene transfer and analysis in rats and mice. The analysis of the PD animal models includes behavioural testing, non-invasive imaging (micro-SPECT, micro-PET and optical imaging), histology and stereological quantifications. In collaboration with Prof. Z. Debyser of the same division in Leuven (Laboratory for Molecular Virology and Gene Therapy), she introduced lentiviral vector technology in Flanders. More recently adeno-associated viral vectors have been added to this viral vector core. Prof. Baekelandt also has a close collaboration with the Center of Excellence MoSAIC at the K.U.Leuven in the area of anatomical and functional imaging in small animals.
Group’s participants. (example)
- Dr Veerle BAEKELANDT, PI - Dr Zeger DEBYSER coPI
- Dr Chris Van den Haute, postdoctoral fellow - Dr. Jean-Marc Taymans, postdoctoral fellow
- Post-doctoral fellow (to be hired) - Bavo Heeman, PhD student
- Mideia Kotsogianni, PhD student - Anke Van der Perren, PhD student
Tasks in the project
- SP2: coordination and performance of WP5: Exploration of the neuroprotective role of parkin and PINK1 in vivo with viral vector technology
Partner 10: Alexander WHITWORTH, University of Sheffield, UK
The University of Sheffield is one of the UK’s leading research-led universities with an international reputation for excellence in research and teaching. Its excellence is reflected in national assessments of university academic performance and the University is among the top ten universities for teaching and research within the UK.
The group of Dr Alex Whitworth is part of the Medical Research Council Centre for Developmental and Biomedical Genetics headed by Prof. Phil Ingham FRS and is affiliated with the Department of Biomedical Science (Head Prof. Matthew Holley). The focus of the MRC Centre is to foster synergy between basic scientists and clinicians in the use of animal models for the understanding and combat or human disease. The laboratory of Dr Whitworth primarily uses the fruit fly, Drosophila melanogaster, as a genetic model to dissect the pathologic mechanisms in PD. They have developed a number of Drosophila models of PD focussing on recessive mutations in parkin, PINK1 and DJ-1. In this project, Dr Whitworth’s group will exploit the powerful genetic approaches in Drosophila to elucidate modifiers of PINK1/Parkin pathology both in vivo and in a cell/RNAi based system. This group will also collaborate with other partners to provide an opportunity to test and validate their novel components, interactors and small molecule compounds in a simple animal model system.
Group’s participants
- Dr Alexander Whitworth PI - Dr Elena Ziviani, Post-doctoral fellow
- Post-doctoral fellow (to be hired) - Technician (to be identified)
- Joe Pogson PhD student
Tasks in the project
- SP1: coordination and performance of WP3: Genetic analysis of PINK1/Parkin function in Drosophila
Partner 11 : Dr. Rebecca PRUSS, Trophos S.A. , France.
Dr. Pruss is the Chief Scientific Officer at Trophos, a French SME. Trophos is a biopharmaceutical company committed to the discovery and development of novel therapeutics to treat neurodegenerative diseases. It was founded in 1999 by a group of entrepreneurs and academic scientists as a spin off of the laboratory of Professor Christopher Henderson, a world expert in motor neuron biology and diseases. Since then, Trophos discovered through its unique phenotypic screening platform a new class of compounds targeting mitochondrial dysfunctions involved in neurodegenerative disorders.
In the MEFOPA project, Dr. Pruss and Trophos’ team will provide their knowledge and know-how on the assessment of mitochondrial dysfunctions through a further exploration of these in the pathophysiology of the Mendelian inherited forms of PD. This will be achieved through the study of mitochondrial activity and changes in the transcriptome in relevant models of the diseases. Should this approach be proven successful, Trophos’ team will then test its mitochondria targeted compounds in these models to assess that such mitochondrial dysfunctions could be amenable to therapeutic intervention.
Group’s participants.
|
- Dr Rebecca Pruss, PhD, PI |
- Dr Magali Michaud, PhD, co-PI |
|
- Dr Caroline Gouarné, PhD |
- Ms Virginie Gourdou Latyszenok |
|
- Post-doctoral fellow (to be recruited) |
- Mr Nicolas Terrayre |
Tasks in the project
- SP2: coordination and performance of WP 4: Assessment of neuroprotective drug effects on the mitochondrial PINK1-parkin pathway
Partner 12: Leonidas STEFANIS, Medical School of The University of Athens, Greece
Dr. Leonidas Stefanis is Associate Professor of Neurology in the Second Department of Neurology of the Medical School of the University of Athens, and Head of the Outpatient Clinic of Memory and Movement Disorders at the “Attikon” Hospital. Dr. Stefanis is also Collaborating Scientist at the Biomedical Research Foundation of the Academy of Athens (BRFAA), where he runs the Laboratory of Neurodegenerative Diseases. The Outpatient Clinic of Memory and Movement Disorders is currently following about 70 patients with Parkinson’s Disease. Dr. Stefanis has received a grant (PENED 2003) from the Hellenic Secretariat of Research and Technology to establish, in collaboration with the Universities of Thessaly and Patras, a database of patients with Parkinson’s Disease in Greece and a DNA biobank of this population in order to ascertain the genetic components of this disorder. In the process of this work, from the population of the Outpatient Clinic of Memory and Movement Disorders, two Parkisnon’s Disease patients with recent onset symptoms were identified as carriers of the A53T AS mutation. Through an extensive net of collaborators across Greece (Univ of Patras, Thessaly and Thessaloniki) a number of other patients with the A53T AS mutation are accessible.
Group’s participants.
- PI: Leonidas Stefanis - Assisting MD: To be hired
- Collaborators: Aglaia Athanassiadou (Univ of Patras), Alekos Papadimitriou (Univ of Thessaly), Sevasti Bostantjopoulou (Univ of Thessaloniki)
Tasks in the project
- SP3: We will recruit and enrol patients with the A53T AS mutation from our own cohort at “Attikon” Hospital, as well as from the patients followed by our collaborators in 3 other Universities in Greece. Genetic testing to confirm the presence of the G209S substitution will be performed at BRFAA. Patients or non-manifesting carriers will be admitted for a one day stay in the Hospital twice, at the beginning and at the end of the study period. All procedures (blood sampling, lumbar puncture, skin biopsy) will be performed in a single day under the supervision of Dr. Stefanis, and with the help of the staff of the Inpatient Unit and an MD who will be paid by the program. Samples will be collected in a standardized fashion and sent to central laboratories for analyses.
Partner 13: Eduardo TOLOSA, Fundació Clinic per a la Recerca Biomèdica (FCRB), Hospital Clinic i Provincial de Barcelona (HCPB), Parkinson disease and Movement Disorders Unit.
Fundació Clínic per a la Recerca Biomèdica (FCRB) was created to manage the research activities of Hospital Clínic i Provincial de Barcelona (HCPB). FCRB has a strong track record of working in European projects, especially within the Framework programme. The European Project Office has a team of dedicated specialist staff to deal with the submission process and negotiation stages and also another sub-department to deal with financial management and project follow-up. In FP5 this office dealt with 30 projects, one of which was coordinated and in FP6 this office dealt with 40 projects, eight of which are coordinated. We are also coordinating 7 projects in FP7.
Our scientific production is very high. In the year 2008, we published 736 original articles, many of which were collaborative studies in which different teams joined their investigative efforts. The actual impact factor of each article is 4.65. The global impact factor for the journals where the abovementioned articles have appeared is 3.420,843 points.
Prof. Tolosa (Parkinson disease and Movement Disorders Unit, Neurology Service) is a neurologist specialized in Parkinson’s disease and related disorders. His research focuses on genetics and clinical areas in PD and Movements Disorders. An intense research about parkin, tau, LRRK2 and other genes have been conducted in PD and other parkinsonisms, sometimes in collaboration with international centres such as the Department of Psychiatry, Washington University School of Medicine, (St. Louis, USA), the Department of Neurology, Mayo Clinic College of Medicine (Jacksonville, USA) and the European Multiple System Atrophy-Study Group (EMSA-SG). His laboratory in collaboration with the University of Barcelona Brain Bank has been concentrated on the characterization of the neuropathology of genetic forms of PD (LRRK2) and the study of brain expression in tauophaties. His interest is now focused on biomarkers in CSF in PD as well in other parkinsonisms. His research team is also focused in the assessment of premotor symptoms in asymptomatic relatives of patients with genetic forms of PD. The research team has a longstanding experience in clinical (such as sleep and neuropsychological studies), diagnostic (like DAT SPECT imaging and Brain MRI) and experimental therapeutics of PD (such as deep brain stimulation and international pharmacological clinical trials).
Group’s participants.
- Dr Eduardo Tolosa, PI
- Dr Mario Ezquerra, Co I; Dr Francesc Valldeoriola, Co I; Dr Maria Jose Martí, Co I; Dr Esteban Muñoz, Co I; Dr Carles Gaig, PhD student; Dr Claustre Pont, PhD student; Dr Pilar Santacruz, Neuropsicologist; Post-doctoral fellow (to be hired); Mr Manel Fernámdez, technician; Technician (to be hired)
Tasks in the project
- SP3: To enrol patients with genetic forms of PD (LRRK2 and Parkin) as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 14: Enza Maria VALENTE, CSS-Mendel Institute, Fondazione Casa Sollievo della Sofferenza Opera di San Pio da Pietrelcina
Dr Valente obtained her Medical Degree at the Catholic University School of Medicine in 1994. She has subsequently trained in Neurology at the same University, attending the services of neurophysiology and movement disorders, and received her certification in Neurology in 1999. She did a PhD in Neurogenetics at the Institute of Neurology, University College of London and obtained her PhD degree in 2003. She has been Head of the Neurogenetics Group at the CSS-Mendel Institute in Rome since 2002 and Associate Professor of Medical Genetics at the University of Messina since 2006. The research activity of her group is focused on the clinical and molecular genetic aspects of movement disorders (mainly Parkinson's Disease and dystonic syndromes), and of congenital cerebellar malformations, and the functional characterization of the PINK1 gene.
Group’s participants
- Dr Enza Maria Valente (PI) - Dr Alessandro Ferraris (coPI)
- Dr Anna Rita Bentivoglio (clinical coordinator) - Dr Monica Bonetti (BSc, research fellow)
Tasks in the project
SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 15: Christine KLEIN, Department of Neurology, University of Luebeck, Germany
Prof. Klein (Department of Neurology, University of Luebeck) is a Lichtenberg Professor of Clinical and Molecular Neurogenetics. She is heading the Interdisciplinary Center of Genetic Movement Disorders at the University of Luebeck and has recently been appointed Full Professor of Neurology within the framework of a new Schilling Department of Clinical and Molecular Neurogenetics at Luebeck University. Prof. Klein is recipient of the Heinrich Pette (2007) and Derek Denny Brown Awards (2008). Her research focuses on the clinical and molecular genetics of movement disorders with a special emphasis on genetic parkinsonism. Prof. Klein’s team consists of three subgroups dealing with the molecular genetics of parkinsonism, its pathophysiological basis in cellular models, and with multimodal neuroimaging/neurophysiology using patients and asymptomatic carriers of ‘PARK’ mutations as a human model of disease.
Group’s participants. (example)
- Prof. Christine Klein, PI - Dr. Katja Lohmann, postdoctoral fellow
- Dr. Slobodanka Orolicki, postdoctoral fellow
- Dr. Johann Hagenah, consultant neurologist
- Dr. Susanne Schneider, movement disorders fellow
- Anne Gruenewald, PhD student - Philip Seibler, PhD student
- Aleksandar Rakovic, PhD student
Tasks in the project
SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 16: José Félix Martí MASSÓ, jefe servicio neurología. Hospital Donostia. San Sebastián.
Prof. Martí Massó (Chief of service of neurology, Hospital Donostia) is a Neuroscientist specialized in Parkinson’s disease and other movement disorders, as well in Dementia. His research focuses on the clinical and genetic aspects of Parkinson’s disease, and therapeutical aspects of neurodegenerative diseases.
Group’s participants. (example)
- Dr. Javier Ruiz Martinez, neurologist
- Dra. Ana Gorostidi Pagola, postdoctoral fellow, Neurogenetics lab.
- Vanessa Blazquez, technician.
Tasks in the project
SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 17: Benjamin BEREZNAI, Maria Judit MOLNAR (head of the departmant), Center for Molecular Neurology, Department of Neurology, Semmelweis University Budapest
The Centre of Molecular Neurology consists of the Neurobiopsy Laboratory, Neurogenetics Laboratory, Neurogenetics Clinics and Inpatient Ward. The head of the department: Maria Judit Molnar MD., PhD, habil. In our department 1 neurologist (Dr. Benjamin Bereznai,PhD) 1 biologist are working with 3 technicians. Furthermore 2 postgraduate PhD students are working with us. The centre has numerous international collaborations. Our scientific activities are focusing on mitochondrial disorders, muscular dystrophies, the establishment of neuropsychiatrical DNA-Tissue- and Fibroblast Bank for pharmacogenetic and epidemiological investigations, screening and investigating of neuromuscular disorders in the Roma population of Hungary, study of genetic background of movement disorders and monogenic Parkinson’s disease, study of coexistence of genetic and immunological changes in hereditary neuropathy as well as study of susceptibility genes in myasthenia gravis, young onset stroke.
Group’s participants.
- Dr Molnar Maria Judit PhD, habil - Dr Benjamin Bereznai, PhD senior researcher
- Gál Anikó, molekular biologist - Magyarósi Szilvia, biobank coordinator
- Dr. Pál Zsuzsanna, Roszkosné - Pentelóenyi Klára, PhD students
Tasks in the project
SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 18: August B SMIT, VUA, Netherlands
Prof. August Smit (Dept of Molecular & Cellular Neurobiology) is a Molecular Neurobiologist with a focus on the dissection of molecular mechanisms of (neurodegenrative) disease, including animal models for Parkinson’s disease. His research focuses on the role of proteins and protein complexes in disease mechanisms using tissue proteomics as a core technology. Dr Connie Jimenez (Co-PI) has developed and implemented robust strategies for biomarker discovery in clinical materials including tumor tissue, biofluids such as blood-serum/plasma, as well as proximal fluids such as cerebrospinal fluid. We have implemented 2 multi-dimensional separation-based workflows: 1. A semi-quantitative workflow consisting of abundant protein depletion followed by label-free profiling using 1D gel coupled to nanoLC-FTMS and 2. A quantitative workflow including isobaric tagging with iTRAQ labels of the depleted CSF peptide mixture followed by 2DLC-MS/MS on MALDI-TOF/TOF. The latter workflow allows for multiplexing up to 8 different patient samples in one analysis and will be used in the current project. In follow-up studies in his laboratory, candidate biomarkers from the discovery phase will be validated in CSF and/or blood by antibody-based techniques.
Group’s participants
Prof. dr. A.B. Smit (supervision/management)
Dr C.R. Jimenez (proteomics facility CSF)
Dr. J. Knol (CSF sample handling & mass spectrometry
Dr. K.W. Li (tissue proteomics, validation & follow-up)
Dr. Van Nierop (Bioinformatics; proteomics information technology)
Vacancy PD (data analysis workflow, antibody generation and testing, validation of markers in larger sample set, tissue proteomics for follow-up
Tasks in the project
SP3: coordination and performance of WP4: Proteomic changes in body fluids and ex vivo cells from patients with rare Mendelian forms of PD
Partner 19: Mathias TOFT, MD PhD, University Hospital Oslo, Norway
Dr. Mathias Toft (Department of Neurology, Centre of Clinical Neuroscience) is a Neuroscientist working predominantly with Parkinson’s disease. His research focuses on genetic causes of Parkinson’s disease and biomarkers of Parkinson’s disease. During his previous period working in Prof. Matthew Farrer’s group at Mayo Clinic Jacksonville (United States) Dr. Toft was participating in a number of genetic studies of Parkinson’s disease. This work identified several genetic mutations inherited as a Mendelian trait, providing important information on disease pathogenesis. Department of Neurology, University Hospital Oslo is a national referral centre for movement disorders, specialised in the treatment of advanced Parkinson’s disease. After moving to University Hospital Oslo, Dr. Toft has been collecting biological material from patients with Parkinson’s disease, their relatives and healthy control individuals. Genetic, genomic and proteomic studies are performed and the data is correlated to clinical information to identify mechanisms of disease and novel diagnostic markers.
Group’s participants
- Dr Mathias TOFT, PI
- Kari Anne Bjørnarå, PhD student/clinical research fellow
- PhD student (to be hired)
- Lena Pedersen, Research nurse
Tasks in the project
SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 20: Dan Healy/ Nicholas Wood, University College London, Institute of Neurology, Queen Square
Prof Wood‘s chief interests are the genetic variants which contribute to nervous system function and dysfunction. Over the last few years our lab and colleagues (within and outside UCL) have built a programme of research based around mendelian genetics and haplotype tagging of the human genome. Currently we are directly involved in 2 genome wide assocaitions studies focussed on two common neurological diseases (Epilepsy and PD).
Dr Healy has recently been appointed Senior Lecturer/Consultant Neurologist at the Royal Free hospitals and Queen Square. His interests include population approaches to neurological diseases and phenotype – genotype correlation especially in Parkinson’s disease and other parkinsonian degenerative disorders.
Group’s participants. (example)
- Dr Dan Healy - Clinical Research Fellow to be hired
- Prof Nicholas Wood - Prof Andrew Lees
- Prof John Hardy - Prof Tamas Revez
- Dr Janice Holton
Tasks in the project
SP3: To enrol patients with genetic forms of PD as well as asymptomatic carriers of such mutations. Obtain blood, CSF and fibroblasts of these individuals.
Partner 21: Omar EL-AGNAF, PhD. Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University.
Dr. Omar El-Agnaf has extensive experience in the cellular and molecular biology of neurodegenerative diseases. He has 15 years experience in this area of research, and has a wide range of expertise including protein chemistry, cell biology and molecular biology. He was the first described (independently of Peter Lansbury’s group) that mutations in α-synuclein protein associated with familial cases of Parkinson’s disease increased the tendency of the α-synuclein protein to aggregate and form amyloid-like fibrils compared to the wild-type protein [El-Agnaf et al., FEBS Lett. 1998]. Recently, his team designed the first peptide-based inhibitors of α-synuclein aggregation and toxicity [El-Agnaf et al., FASEB; 2004]. Dr. El-Agnaf’s group is also actively engaged in biomarkers discovery for Parkinson’s disease. His group has discovered the unexpected identification of α-synuclein protein in conditioned culture media from neuronal cells, as well as in human cerebrospinal fluid and blood plasma [El-Agnaf et al., FASEB; 2003; 13:1945-7]. This discovery has led to the hypothesis that α-synuclein is normally released by the neuronal cells into the surrounding media and that the concentration levels of the extracellular α-synuclein and/or its modefied forms might be altered in the CSF and blood of patients with PD and related diseases [El-Agnaf et al., FASEB; 2003; Lancet Neurol. 2003], and his group has pioneered the investigations for testing alpha-synuclein protein and its derivatives as potential biomarker for Parkinson’s disease and related disorders. His laboratory has developed the first and most sensitive ELISA methods for measuring alpha-synuclein protein in human biological fluids [Tokuda et al., BBRC. 2006; 349:162-6; Mollenhauer et al., Exp Neurol. 2008; 2:315-25]. Furthermore, Dr. El-Agnaf’s team has developed specific and sensitive novel ELISA method that detects only alpha-synuclein oligomers in human plasma and CSF [El-Agnaf et al., FASEB J. 2006; 3:419-25]. His group also developed promising imaging agents for PD animal model using noninvasive MRI technology.
Group’s participants. (example)
- Dr. Omar El-Agnaf, PI - Post-doctoral fellow (to be hired)
Tasks in the project
- SP3: coordination and performance of WP5: Determination of a-synuclein species in biological fluids
5 Publications relevant to the project
K. E. Paleologou, C.L. Kragh, D.M. A. Mann, S.A. Salem, R. Al-Shami, D. Allsop, A.H. Hassan, R.M. Bernsen, P.H. Jensen, O.M. A. El-Agnaf (2008). Detection of elevated levels of soluble α-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain (Accepted for publication).
B. Mollenhauer, V. Cullen, I. Kahn, B. Krastins,T.F. Outeiro, I. Pepivani, J Ng, W. Schulz-Schaeffer, H.A. Kretzschmar, P.J. McLean, C. Trenkwalder, D.A. Sarracino, J.P. Vonsattel, J.J. Locascio, O.M.A. El-Agnaf, M.G. Schlossmacher. (2008). Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2:315-25.
T. Tokuda, S.A. Salem, D. Allsop, T. Mizuno, M. Nakagawa, M.M. Qureshi, J.J. Locascio, M.G. Schlossmacher and O.M.A. El-Agnaf (2006). Decreased α-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease. Biochem Biophys Res Commun. 349: 162-166.
O.M.A. El-Agnaf, S.A. Salem, K.E. Paleologou, M.D. Curran, M.J. Gibson, J.A., J.A. Court, S.G. Michael and D. Allsop (2006). Detection of oligomeric forms of α-synuclein protein in cerebrospinal fluid and plasma as a potential biomarker for Parkinson’s disease. FASEB J. 20: 419-425.
O.M.A. El-Agnaf, S.A. Salem, K.E. Paleologou, L.J. Cooper, N.J. Fullwood, M.J. Gibson, M.D. Curran, J.A. Court, S. Ikeda, M.R. Cookson, J. Hardy and D. Allsop (2003). α-Synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB Journal, 13: 1945-1947.