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An integrated approach towards understanding the pathogenesis of CNS and PNS neurodegenerative disorders

Research project P6/43 (Research action P6)

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Description :

The proposed network brings together researchers specialized in clinical neurology, neuropathology, genetics and genomics, cell biology, mouse and small model organisms, and protein modelling, who are active in the domain of neurodegenerative diseases. The network will focus its research activities on these neurodegenerative diseases, comprising diseases of the central nervous system (CNS) such as Alzheimer disease, Parkinson disease, frontotemporal dementia and related diseases; and diseases of peripheral nervous system (PNS) such as peripheral motorneuronopathies, amyotrophic lateral sclerosis and related disorders.

The network consists of 8 partner groups that together represent the leading teams active in neurodegenerative research in Belgium. The network also liaisons with three leading teams of the Netherlands (Rotterdam) and Germany (Aachen and Kiel). Several of these groups have received worldwide recognition for their work, as exemplified by major research prizes, publications in top-tier journals, international funding (e.g. EU) and participations in international networks. Furthermore, approximately half of the principal investigators in this network are either young leaders or newly integrated groups. Several of these investigators recently returned to Belgium after prolonged stays abroad to start their research groups in Belgium. Thus, next to the ambitious scientific objectives of the network, we also aim at integrating these young and new groups into a major scientific network, providing them access to major research infrastructure present in established groups, creating and fostering scientific interaction and training, and in doing so, increasing the visibility of major research efforts in Belgium to increase our understanding of these debilitating diseases.

The partners aim at clarifying a series of fundamental questions related to the pathophysiological processes underlying these diseases. More specifically, they aim at identifying biological pathways that are linked to these diseases, by identifying novel genes and genetic risk factors, by identifying modifiers of genetic function by genetic screens, by analyzing the functional networks in which the proteins encoded by these genes are operating, and ultimately, by providing novel avenues for early diagnosis, prognosis, prevention and treatment.

While neurodegenerative diseases represent a heterogeneous mix of pathological entities, over the last years it has become obvious that several recurrent themes appear in all these entities. All compromise the nervous system, are usually characterized by a later age of onset, present with synaptic dysfunction, and many of them are characterized by biochemical abnormalities, such as abnormal cellular “inclusions” or accumulation of peptides. From a mechanistic point of view, neuronal function is jeopardized by axonal transport problems, mitochondrial dysfunction, nerve conductance or neurotransmission deficiencies, or increased vulnerability to cellular stress resulting in apoptosis. Moreover, technological approaches in the different disease domains overlap considerably, and for these two reasons – i.e. conceptually at the scientific level and practically at the experimental level – we brought together these teams in an integrated network. While the scientific interaction is usually more difficult to steer in a top down approach, the technological interaction is an almost natural way of organizing different groups in a network, and we therefore defined 8 workpackages covering the different steps of the workplan we want to develop over different areas. These work packages are (1) Clinical neurology, (2) Neuropathology (3) Genetics and genomics (4) Cell Biology (5) Mouse modelling (6) Small model organisms (7) Protein modelling and (8) Therapeutics. In each work package, several research teams are involved with specific additive or complementary expertise in defined areas. We expect that interactions between these groups will provide a significant and critical mass needed to address the main research questions of the project.

Scientifically, we believe that these interactions will enormously enhance the impact of the different research groups in their own domain. For instance, theoretical models of protein aggregation developed in the protein modelling group with their major expertise in biophysics can be tested by partners in cell biology or animal models. Similarly, as demonstrated in the previous network (IAP5 - network P19), the interaction between geneticists and cell biologists can be extremely fruitful and effective. We believe that the focus of the current network on “neurodegenerative disease”, as opposed to “genetic disease” in the previous network, provides sufficient narrow focus and common interest to optimally foster cross-border interests and interactions. On the other hand, by including several neurodegenerative diseases, concepts arising in different areas of research can influence and broaden the view of the individual research groups.

In conclusion, this network proposes a major research effort into the understanding of neurodegenerative diseases by bringing together a number of excellent research groups in Belgium and Europe, creating a virtual research department providing an international competitive critical mass in this research area.

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