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Peripheral Neuropathies Group
Main organisation:Department of Biomedical Sciences
Lifecycle:1 Oct 2003 → Today
Organisation profile:State of the art Inherited peripheral neuropathies belong to the most common neuromuscular disorders and occur worldwide (1/2500). The best known is Charcot-Marie-Tooth disease (CMT), an inherited disorder first described in 1886. Most patients have a progressive weakness and wasting of foot and hand muscles. Sometimes patients need walking aids or become wheelchair dependent even at a young age. The clinical variability and genetic heterogeneity often poses difficult diagnostic problems. Treatment is currently supportive (braces and foot surgery) and a therapy that fundamentally alters the course of these diseases is still lacking. A better understanding of the molecular architecture of the peripheral nerve, the functional pathways, the myelination process and the complex interaction between the axon, the myelinating Schwann cells and muscle is crucial to identify targets for therapeutic interventions. The identification of loci, genes and disease-causing mutations involved in the inherited peripheral neuropathies is the first step in this understanding and opens new perspectives for molecular genetic diagnosis. Genotype/phenotype correlations guide the selection of specific mutations suitable for functional analysis in cellular and animal models. These models are instrumental in the search for therapies. The knowledge gained from the molecular genetic and biological research of inherited peripheral neuropathies will also help to make progress in the study of acquired peripheral neuropathies. Some of these neuropathies are often therapy-resistant, have a profound influence on the quality of life of the patients, and constitute a financial burden for both the individual and the community.StrategyThe peripheral nervous system (PNS) exchanges motor, sensory and autonomic information between the central nervous system (CNS) and the limbs, organs and tissues. A series of biological and environmental conditions, such as genetic mutations, chemical stress, infections or metabolic insults, can lead to axonal loss and demyelination, the pathological hallmarks of peripheral nerve degeneration. Moreover, degeneration of peripheral nerves is accompanied by a local activation of the immune system. The Peripheral Neuropathy Group aims at understanding the delicate balance between peripheral nerve homeostasis and degeneration by using two paradigms: (1) how do genetic mutations lead to peripheral nerve degeneration and (2) what is the role of the innate immune system in nerve protection. ScienceOver the years, our lab has become one of the main CMT research centers in the world; overall, 1/3 of the 40 IPN disease causing genes were found within our team or via international collaborations. Not surprisingly, many of these genes encode proteins that are involved in myelination and maintenance of the peripheral nerve. However, also ubiquitously expressed genes with basic tasks in every cell were found to specifically cause peripheral nerve degeneration.Since the identification of a disease-associated gene is only a first step in unraveling the disease pathomechanism, we aim to go further and understand the functional consequences of the pathogenic mutations. We chose to focus on genes that our lab identified to be causative for CMT. We aim to unravel the unique properties of these proteins in peripheral nerve biology as well as explore how these properties are affected upon mutation. To this end, we develop cellular and animal model systems. We are not only investigating the impact of disease-causing mutations on the well established functions of these proteins, but additionally try to identify novel pathways in which these proteins might be involved by undertaking large scale approaches. Our 'gene-driven' approach is further complemented by a second research line, which aims to identify the role of the innate immune system in neuroprotection and -degeneration. Understanding how this balance is controlled might allow us to fine-tune or even stimulate an inherent neuroprotective response.We strongly believe that our research strategy can contribute to the development of novel treatment strategies for CMT patients. The interaction between neurologists, molecular geneticists and cell biologists places our lab in a privileged position: it ensures access to patient material, and also allows us to couple back our findings in the lab with clinical data. We also maintain contacts with the International CMT Consortium by co-organising meetings and workshops.
Keywords:ANIMAL MODELS, CHARCOT-MARIE-TOOTH DISEASE, CELLULAR MODELSYSTEMS, MOLECULAR GENETICS, INHERITED PERIPHERAL NEUROPATHIES
Disciplines:Genetics, Systems biology, Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing