3rd EURASNET WP12 IFM Meeting on Alternative and Aberrant Splicing in Neuromuscular and Neurodegenerative Processes
26-27 March, 2009
ICGEB Trieste, Italy
Meeting Report
EURASNET Workshop on Alternative Splicing
The workshop was organised by Prof. Francisco E. Baralle, Eurasnet WP 12 coordinator with the following aims:
· Get together molecular biologist, neurobiologists and clinical neurologists to discuss the impact of RNA processing derangements in neuromuscular and neurodegenerative diseases
· Assess the future strategies for a target design therapy of these pathologies;
· Highlight the need for increased interdisciplinary research in this area;
· Obtain an up-to-date overview of current research in Europe of hnRNPs such as TDP 43 and FUS that have been shown to be involved in pathologies such as ALS and FTLD and are now been described in other neurodegenerative diseases.
The workshop consisted of a series of seminars from EURASNET members and invited speakers. The Workshop was organized as a two-day meeting in order to provide several communal coffee and buffet breaks that allowed the participants to discuss and comment on the attended presentations.
The seminars (Annex I) were designed to provide an introduction to alternative splicing in a variety of neuromuscular and neurodegenerative diseases, both from a clinical to a basic science research point of view.
Clinical presentations. Prof. John Van Swieten and Prof. Christoper Shaw (Erasmus Medical Centre, Rotterdam and MRC Centre for Neurodegeneration Research, London, respctively) gave an overview of the clinical genotype-phenotype correlations in Frontotemporal dementias. In particular, Prof. Chris Shaw also reported his account of his recent discovery, recently published in Science, regarding the involvement of a new hnRNP protein (FUS/TLS) in familial ALS cases. Following these presentations, Maria Grazia Spillantini, from the Univ. of Cambridge, extended these overviews from the FTLD/ALS pathologies to Tau-mediated neurodegenerative diseases, a topic that was also discussed later on by Jean Marc Gallo from the MRC Centre for Neurodegeneration Research, London) with particular emphasis on the analysis of tau mutants. Finally, Manuela Neumann from the Institute of Neuropathology, Zurich, Switzerland gave a lecture on the clinical genotype-phenotype correlations of FTLD with particular attention to her 2006 discovery of TDP-43 involvement in these diseases. Her talk was complemented by Stuart-Pickering Brown (University of Manchester, UK) who addressed the question of additional still unidentified markers underlying the occurrence of FTD diseases in the general population.
Basic science presentations. The predominantly clinical talks shortly summarized in the previous section were complemented by a series of lectures more focused on the potential biomolecular mechanisms of disease. In addition, several lectures also focused on the most recent attempts to actually target these diseases with a series of therapeutic strategies based on correcting aberrant alternative splicing.
With regards to the involvement of TDP-43 in FTD/ALS both Prof. Baralle and Dr. Buratti (ICGEB, Trieste) presented their latest data on TDP-43 research with regards to the control of alternative splicing by TDP-43 and its potential involvement with microRNA control and neurodegeneration, respectively. Similarly, Dr. Fabian Feiguin (ICGEB Trieste) completed these lectures by ICGEB researchers describing his recently developed Drosophila animal model that lacks the homologue of TDP-43 and displays several neuromuscular junction defects. In this respect, of particular interest were also the lectures from Christian Haas and Bettina Schmidt (Ludwig Maximilians University, Munich, Germany) who reported an investigation of the TDP-43 proteolytic processing in neurodegeneration and the attempt to develop a TDP-43 based zebrafish model of the disease. Finally, these talks dealing predominantly with TDP-43 were completed the lecture of Jernej Ule (MRC Laboratory of Molecular Biology, Cambridge, UK) that reported his preliminary data on his UV-crosslinking and immunoprecipitation (CLIP) technique to identify in vivo TDP-43 RNA targets in human brains.
With regards to neuromuscular degeneration, Dr. Davide Gabellini (DIBIT-HSR, Milan, Italy) gave a lecture with regards how recent data from his lab suggest that aberrant alternative splicing could explain the peculiar involvement of specific muscle groups in Facioscapulohumeral Muscular Dystrophy (FSHD) whilst Dr. Antoine Clery (Institute of Molecular Biology and Biophysics, ETH, Zurich, Switzerland) reported his latest NMR structural studies of human tra2beta1 and SF2/ASF, two factors involved in the alternative splicing of SMN.
In parallel, considerable attention has also been paid to potential RNA splicing based therapeutic approaches to neuromuscular diseases. In particular, Dr. Matthew J.A. Wood (University of Oxford, UK) described a splice correction therapy for Duchenne Muscular Dystrophy based on the use of antisense oligos to cause exon skipping in patient's muscle tissue to recover dystrophen protein functionality and Prof. Daniel Schümperli (Institute for Cell Biology, Bern, Switzerland) described the current prospects for a U7 snRNA-based gene therapy in the cure for Spinal Muscular Atrophy.
Reaction to the Workshop
All participants (Annex II) have expressed considerable interest and excitement in the areas covered by the Meeting and all agree that alternative splicing as a potential cause of neurodegeneration is a very appealing future research area. Contacts are currently taking place between many participants to work together on particular alternatively spliced genes and events.
Conclusions
The IFM Meeting fulfilled all of its objectives in raising awareness of the importance of alternative and aberrant splicing occurrence in neurodegenerative diseases. The mix of presentations by basic molecular biologists and clinicians was extremely valuable to identify potential areas of common interest and to identify the most promising future lines of basic research and therapy.
ANNEX I
PROGRAMME OF THE IFM
26 March 2009
“The Clinical Settings in Neuromuscular and Neurodegenerative Processes”
Chairperson: Dr Diana Baralle (Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK)
15:00 Registration
15:30 Prof. Christopher E. Shaw (MRC Centre for Neurodegeneration Research, London, UK)
“Aberrant RNA processing in motor neuron disorders”
16:00 Dr. John C. van Swieten (Erasmus Medical Center, Rotterdam, The Netherlands)
"Genotype-phenotype correlations in hereditary Frontotemporal Dementias"
16:30 Dr. Matthew J.A. Wood (University of Oxford, UK)
“Splice correction therapy for Duchenne Muscular Dystrophy”
17:00 Prof. Maria G. Spillantini (University of Cambridge, UK)
“Mechanisms of tau dysfunction in neurodegenerative diseases”
17:30 Break
18:00 Prof. Daniel Schümperli (Institute for Cell Biology, Bern, Switzerland)
“Prospects for a U7 snRNA-based gene therapy for Spinal Muscular Atrophy”
18:30 Prof. Vincenzo Silani (University of Milan, Medical School, IRCCS Istituto Auxologico Italiano, Milan, Italy)
“New approach to the patient with neurologic disease: locate the gene(s)”
“The Molecular Biology of Neuromuscular and Neurodegenerative Processes” part I
Chairperson: Prof. Francisco Baralle (ICGEB, Trieste, Italy)
19:00 Dr. Jean M. Gallo (MRC Centre for Neurodegeneration Research, London, UK)
“Tau alternative splicing in neurodegeneration: mechanisms and therapeutic strategies”
19:30 Dr. Manuela Neumann (Institute of Neuropathology, Zurich, Switzerland)
“Molecular Neuropathology of TDP-43-proteinopathies”
20:00 Get together buffet
21:00 Bus to hotel
27 March 2009
“The Molecular Biology of Neuromuscular and Neurodegenerative Processes” part II
Chairperson: Dr Fabian Feiguin (ICGEB, Trieste, Italy)
8:00 Bus to ICGEB
8:45 Prof. Stuart Pickering-Brown (University of Manchester, UK)
"Molecular mechanisms underlying Frontotemporal Lobar degeneration"
9:15 Prof. Christian Haass (Ludwig Maximilians University, Munich, Germany)
“Proteolytic processing in neurodegeneration”
9:45 Dr. Antoine Clery (Institute of Molecular Biology and Biophysics, ETH, Zurich, Switzerland)
"NMR structural study of human tra2beta1 and SF2/ASF, two proteins involved in the alternative splicing of
SMN"
10:00 Prof. Francisco Baralle (ICGEB, Trieste, Italy)
“Dissection of TDP43 functional interactions”
10:30 Dr. Jernej Ule (MRC Laboratory of Molecular Biology, Cambridge, UK)
“UV-crosslinking and immunoprecipitation (CLIP) identifies TDP-43 RNA targets in human brain”
11:00 Break
11:30 Dr. Emanuele Buratti (ICGEB, Trieste, Italy)
“Is the interaction between the microprocessor complex and TDP-43 functional?”
12:00 Dr. Isabelle Behm-Ansmant (Université Henri Poincaré, Vandoeuvre les Nancy, France)
“DM1 and DM2 and the MBNL1 splicing factor”
“Cell and Developmental Biology of Neuromuscular and Neurodegenerative Processes”
Chairperson: Dr Emanuele Buratti (ICGEB, Trieste, Italy)
12:15 Dr. Davide Gabellini (DIBIT-HSR, Milan, Italy)
“Alternative splicing could explain the peculiar involvement of specific muscle groups in Facioscapulohumeral Muscular Dystrophy (FSHD)”
12:45 Dr. Fabian Feiguin (ICGEB, Trieste, Italy)
“Genetic analyses of TDP-43 function in vivo”
13:15 Dr. Bettina Schmid (Ludwig Maximilians University, Munich, Germany)
“Analysis of TDP-43 in Zebrafish”
13:45 Lunch
15:00 End of the meeting and bus to hotel
ANNEX II - Participants
Prof. Frédéric Allain
Institute of Molecular Biology and Biophysics
Zürich
Switzerland
Dr Karen Anthony
MRC Centre for Neurodegenerative Research
King's College London, Institute of Psychiatry
Dept. of Clinical Neuroscience
London
UK
Ms Chiara Appocher
Neurobiology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Selma Eréndira
Avendaño Vázquez Neurobiology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Yuna Ayala
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr Diana Baralle
Wessex Clinical Genetics Service
Princess Anne Hospital
Southampton
UK
Prof. Francisco E. Baralle
Director-General and Head, Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Marco Baralle
Biotechnology Developmnet Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr Isabelle Behm-Ansmant
UMR 7567
Faculté des Sciences et Technique
Université Henri Poincaré
Vandoeuvre-les-Nancy
France
Dr Amit Berson
The Hebrew University of Jerusalem
Dept. of Biological Chemistry
Jerusalem
Israel
Dr Ron Bochner
Tel-Aviv University
Sackler Faculty of Medicine
Dept. of Molecular Genetics and Biochemistry
Tel-Aviv
Israel
Dr Dario Bossi Studio Medico
Trieste
Italy
Dr Christiane Branlant
Laboratoire AREMS, UMR 7567, CNRS-UHP
Faculté des Sciences et Technique
Université Henri Poincaré
Vandoeuvre-les-Nancy
France
Dr. Mauricio Budini
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Emanuele Buratti
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Yari Carlomagno
Human Genetics Laboratory
Department of Medical Sciences
University of Eastern Piedmont "A. Avogadro"
Novara
Italy
Dr. Antoine Clery
Institute of Molecular Biology and Biophysics
Zürich
Switzerland
Dr Claudia Colombrita
Dept. of Neuroscience
IRCCS Istituto Auxologicao Italiano
Università degli Studi di Milano
Cusano Milanino (MI)
Italy
Dr. Lucia Corrado
Human Genetics Laboratory
Department of Medical Sciences
University of Eastern Piedmont "A. Avogadro"
Novara
Italy
Dr. Luisa Costessi
Mouse Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Andrea D'Ambrogio
Proteomics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Laura De Conti
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr Dorothee Dormann
Ludwig Maximilians University
Adolf-Butenandt-Institute
Department of Biochemistry
Munich
Germany
Ms Alessia Falanga
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Fabian Feiguin
Neurobiology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Mr Eugenio F. Fernandez
Human Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Davide Gabellini
Division of Regenerative Medicine, San Raffaele Scientific Institute, DIBIT
Milan
ITALY
Dr. Jean-Marc Gallo
MRC Centre for Neurodegeneration Research
Institute of Psychiatry
Department of Clinical Neuroscience
King's College London
UK
Mr Vinay Kumar Godena
Neurobiology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Elisa Goina
Human Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Prof. Christian Haass
Ludwig Maximilians University
Adolf-Butenandt-Institute
Department of Biochemistry
Munich
GERMANY
Dr Hadas Keren
Tel-Aviv University
Sackler Faculty of Medicine
Dept. of Molecular Genetics and Biochemistry
Tel-Aviv
Israel
Ms Raffaella Klima
Neurobiology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr Malgorzata Konieczna
Adam Mickiewicz University
Dept. of Gene Expression
Institute of Molecular Biology and Biotechnology
Poznan
Poland
Dr Pietro Laneve
Institute of Molecular Biology and Pathology, CNR
La Sapienza University
Rome
Italy
Dr Diego Marega
Clinic of Urology
Cattinara Hospital
Trieste
Italy
Dr Nathalie Marmier-Gourrier
UMR 7214
Faculté des Sciences et Technique
Université Henri Poincaré
Vandoeuvre-les-Nancy
France
Dr Alexandra Martins
INSERM U614
Faculté de Médecine ed Pharmacie
Rouen
France
Dr. Andres F. Muro
Mouse Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Ms Mirjana Nedeljkovic
Mouse Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Manuela Neumann
Institute of Neuropathology
Zurich
Switzerland
Dr. Franco Pagani
Human Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Ms Monica Passoni
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr Izabela Pasternak
Adam Mickiewicz University
Dept. of Gene Expression
Institute of Molecular Biology and Biotechnology
Poznan
Poland
Mr Tibor Pastor
Human Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Prof. Stuart Pickering-Brown
Clinical Neurosciences
University of Manchester
UK
Dr Dorota K. Raczynska
Adam Mickiewicz University
Dept. of Gene Expression
Institute of Molecular Biology and Biotechnology
Poznan
Poland
Dr Michela Raponi
University of Southampton
Human Genetics
Southampton
UK
Dr Antonia Ratti
Dept. of Neuroscience
IRCCS Istituto Auxologicao Italiano
Università degli Studi di Milano
Cusano Milanino (MI)
Italy
Prof. Janice Robertson
Centre for Research in Neurodegenerative Diseeases
University of Toronto
Toronto, Ontario
Canada
Dr. Bettina Schmid
Ludwig Maximilians University
Adolf-Butenandt-Institute
Department of Biochemistry
Munich
Germany
Prof. Daniel Schümperli
Institute for Cell Biology
Bern
Switzerland
Prof. Christopher E. Shaw
MRC Centre for Neurodegeneration Research
Department of Clinical Neuroscience
Institute of Psychiatry
King's College London
UK
Prof. Maria Grazia Spillantini
Department of Clinical Neurosciences
University of Cambridge
Centre for Brain Repair
Cambridge
UK
Dr Karol Szafranski
Fritz Lipmann Institute
Institute for Age Research
Genome Analysis
Jena
Germany
Ms Claudia Tammaro
University of Southampton
Southampton General Hospital
Southampton
UK
Dr James Tollervey
MRC Laboratory of Molecular Biology
Structural Studies Division
Cambridge
UK
Mr Enrico Tongiorgi
B.R.A.I.N. Centre for Neuroscience
Dept. of Life Sciences
University of Trieste
Italy
Ms Ifeoma Ubby
Human Molecular Genetics Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Dr. Jernej Ule
MRC Laboratory of Molecular Biology
Cambridge
UK
Dr. John C. van Swieten
Department of Neurology
Erasmus Medical Centre Rotterdam-Dijkzigt
THE NETHERLANDS
Dr Zhen Wang
MRC Laboratory of Molecular Biology
Structural Studies Division
Cambridge
UK
Dr. Matthew J.A. Wood
Department of Physiology
Anatomy and Genetics
University of Oxford
UK
Dr Shangxi Xiao
Centre for Research in Neurodegenerative Diseeases
University of Toronto
Toronto, Ontario
Canada
Ms Paola Zago
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy
Ms Lorena Zubovic
Molecular Pathology Group
International Centre for Genetic Engineering and Biotechnology – ICGEB
Trieste
Italy