The Helmholtz Virtual Institute „RNA dysmetabolism in ALS and FTD“

The Helmholtz Virtual Institute “RNA dysmetabolism in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)” was established in October 2012 and is one of over 100 Virtual Institutes that are funded by the Helmholtz Association. In these Virtual Institutes new research collaborations are established that merge the expertise of Helmholtz Centers with German universities and additional associated national and international partners on significant fields of research. The institutes are funded over a period of three to five years with up to 600.000 Euro yearly from the Initiative and Networking Fund.

The German Center for Neurodegenerative Diseases (DZNE) regards ALS and FTD as neurodegenerative diseases with substantial medical and scientific significance with respect to the mission of the DZNE. Research in this field has been successively expanded; lastly by recruiting Prof. Manuela Neumann to Tübingen in June 2012. Currently, research on ALS and FTD is carried out in Dresden, Munich, and Tübingen. In the Virtual Institute „RNA dysmetabolism in ALS and FTD“, ongoing research at the DZNE was brought together with the internationally recognized competence in the area of ALS and FTD of the Ulm University as well as of the Universities of Strasbourg (France) and Umeå (Sweden). The University Ulm is internationally regarded as one of the most significant clinical research institutes in ALS and FTD, whose expertise ranges from basic research to highly specialized care for patients. Its neurobiobank comprises about 4000 patient-specific cell lines and 1000 blood and liquor samples. Together with the associated partners in Umeå and Strasbourg, one of the worldwide largest biobanks is available for research on ALS and FTD.

Research objective

Our scientific goal is to clarify the role of dysfunctional RNA metabolism in ALS and FTD with respect to the underlying mechanisms and the consequences for function and survival of nerve cells. In more detail, we want to investigate the pathomechanism of ALS and FTD linked mutations in FUS and C9ORF72 as well as the fundamental cell biological functions of these genes under physiological conditions, in particular with regard to cell metabolism and synapse formation.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease with a prevalence of 6-8 in 100 000 people and occurs between the age of 40 and 80. ALS is characterized by the degeneration of upper motor neurons within the motor neocortex and the lower motor neurons in the brainstem and spinal cord that innervate muscle fibers. Their degeneration leads to a progressive muscle weakness and atrophy and thus palsy with primary distal limb or bulbar (speech and swallowing, about 1/4 of cases) onset. Most ALS patients die within 3 to 5 years after symptom onset from respiratory failure. About 5-10% of all cases are hereditary (familial ALS, FALS) in contrast to sporadic ALS (SALS).

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by a progressive atrophy of the frontal and temporal lobes of the forebrain. FTD accounts for up to 15% of all dementia cases and thus is the third most common form of dementia behind Alzheimer’s disease and vascular dementia, and in the range of dementia with Lewy bodies. FTD occurs between the mid 40s and mid 60s of age and presents in grave personality changes and behavioral abnormalities including loss of social awareness, blunted emotionality and/or language impairment. 30-40% of all FTD cases are hereditary, thus called familial FTD.

Fuelled by new findings, the idea strengthened that pure forms of ALS and FTD can be regarded as the ends of a spectrum of one condition. In fact, 15% of ALS patients have FTD and vice versa (ALS-FTD) and patients which have primarily ALS or FTD can display various degrees of clinical symptoms resembling those of the respective other disease.

Neuropathological hallmarks of the overlapping diseases represent ubiquitin-positive neuronal cytoplasmic inclusions (NCIs) composed of protein aggregates that contain TDP-43 (FTD/ALS-TDP) or FUS (ALS/FTD-FUS, tau aggregates can be found in non-overlapping FTD: FTD-tau). These pathologies appear in conjunction with distinct gene mutations: while mutations in genes for C9ORF72, GRN (Progranulin), TARDBP (TDP-43), and VCP cause TDP pathology, only FUS gene mutations lead to FUS bearing NCIs. Most recently discovered mutations in ALS and FTD are linked to RNA metabolism, either in form of mutated RNA binding proteins (TDP-43, FUS) or in form of a potential toxic RNA product (hexanucleotide repeat expansions of C9ORF72). This suggests that a disturbed RNA metabolism is involved in the etiology of ALS and FTD.

Scientific program

1. Cellular models of FUS and C9ORF72 in neurodegeneration

  • Tobias Böckers (Ulm University)
  • Andreas Hermann, Alexander Storch (DZNE Dresden)
  • Gerd Kempermann (DZNE Dresden)
  • Peter Andersen (University of Umeå)

Here, the aim is to use stem cells to elucidate fundamental biological functions of the FUS and C9ORF72 in RNA metabolism and the consequences of their disease-related mutations in motoneuron degeneration and dementia. Somatic stem cells from mice and humans as well as ALS patient-specific iPS cell lines will be used to elucidate the role of FUS and C9ORF72 in stem cell function, neurogenesis, motoneuron development and degeneration, and the potential usefulness of these genes as targets for therapeutic or preventive intervention.

2. Effect of RNA-related ALS gene mutations on energy metabolism

  • Anke Witting, Patrick Weydt (Ulm University)
  • Katrin Lindenberg (Ulm University)
  • Philipp Kahle (DZNE Tübingen
  • Alexander Storch, Gerd Kempermann, Andreas Hermann (DZNE Dresden)
  • Luc Dupuis, Jean-Philippe Loeffler (Inserm U692, Université Strasbourg )

Our goal is to study and compare effects of the mutations in FUS, TDP43 and C9ORF72 on energy metabolism with the underlying hypothesis that defects in the pathways that control RNA metabolism will be critical for energy metabolism in ALS (and FTD) pathogenesis. Since effects of TDP43 on mitochondrial morphology are known, we will focus on mitochondrial metabolism.

3. Synaptogenesis and synaptic plasticity

  • Tobias Böckers (Ulm University)
  • Alexander Storch, Andreas Hermann (DZNE Dresden)

Our aim is to further elucidate the extranuclear role and transport dynamics of FUS (including mutated FUS), with a focus on morphology and plasticity at excitatory synapses and neuromuscular junctions. We will investigate the interaction of FUS with Dynactin, an ALS-related protein that binds to microtubles and dynein. What is the functional role and importance of the interaction? Can mutations in Dynactin influence the functions or the subcellular localization of FUS or other RNA-binding proteins? In addition we pursue the initial characterization of C9ORF72 in primary neuronal cultures. Can a synaptic distribution of the protein be confirmed and what are the functional consequences?

4. Role of other protein deposits and co-aggregates in ALS and FTD

  • Manuela Neumann (DZNE Tübingen)
  • Christian Haass (DZNE München)
  • Philipp Kahle (DZNE Tübinen)

The major aim here is to gain more insight into the full protein composition/proteome of the inclusions among the various forms of FUS-opathies and C9ORF72-linked TDP-opathies. This will allow us to address the important question whether sequestration of other proteins and their subsequent functional depletion in neurons and glial cells is involved in FUS and C9ORF72- mediated neurodegeneration. Identification of co-aggregated proteins will not only help to elucidate the pathomechanisms underlying cell death in these conditions but might also lead to the identification of promising novel targets for further therapeutic and biomarker approaches.

Participants

  • DZNE Dresden:

Prof. Dr. Gerd Kempermann
Site Speaker

Prof. Dr. Alexander Storch
Group Leader

Dr. Dr. Andreas Hermann
Co-group leader & Senior neurologist at TU Dresden 

  • DZNE Munich:

Prof. Dr. Dr. Christian Haass
Site Speaker

  • DZNE Tübingen:

Prof. Dr. Manuela Neumann
Group Leader

Prof. Dr. Philipp Kahle
Group Leader at DZNE and Hertie Institute 

  • German University Partner: University of Ulm

Prof. Dr. Albert C. Ludolph
Director and chair, Department of Neurology  

Dr. Katrin S. Lindenberg
Senior Post-Doc, Department of Neurology, Experimental Neurology, Biomedical Research Center

Dr. Patrick Weydt
Neurologist, Department of Neurology

Dr. Anke Witting
Group Leader, Experimental Neurology, AG Neuroinflammation, Center for biomedical research

Prof. Dr. Tobias M. Böckers
Director of Institute, Institute for Anatomy & Cell Biology

  • International Partners:

Prof. Dr. Jean-Philippe Loeffler
Group Leader, Mécanismes Centraux et Périphériques de la Neurodégénérescence
Inserm U692
Faculté de Médecine, Université de Strasbourg

Prof. Dr. Luc Dupuis
Senior Research Associate, Group Leader
Mercator professor at University of Ulm,
Mécanismes centraux et périphériques de la neurodégénérescence
INSERM U1118
Faculté de Médecine, Université de Strasbourg

Prof. Dr. Peter M. Andersen
Group leader, Guestprofessor at Ulm University  
Department of Neurology Umeå University Hospital NUS SE-90185 Umeå, Sweden

News

Structure

Steering Committee:
Gerd Kempermann, DZNE Dresden, Speaker of Virtual Institute
Albert Ludolph, Ulm University, Vice-Speaker, Speaker of the University Partner
Christian Haass, DZNE München
Manuela Neumann, DZNE Tübingen

Coordination:
Dr. Annette Rünker
Virtual Institute „RNA dysmetabolism in ALS and FTD“
German Center for Neurodegenerative Diseases (DZNE)
Arnoldstr. 18
01307 Dresden

annette.ruenker(at)dzne.de
+49 (0) 351 / 210-463-21
+49 (0) 351 / 210 463-99