Molecular pathomechanisms of HSPB1 and HSPB8 mutations in motor neuropathies: study of protein-protein interactions and axonal transport in cellular and animal models.

Through positional cloning, more that 30 disease-associated genes where indentified as the cause of hereditary neuropathies of the peripheral nervous system (PNS). Many of these genes encode proteins that play an essential role in RNA processing, protein synthesis, cell death and/or cellular stress reactions. Apparently, the neurons of the PNS are very sensitive to mutations in these genes possibly due to the fact that these neurons have long axons with a very high metabolic demand for the axonal transport of cellular components over very long distances. This project investigates the pathogenic mechanism underlying the neuronal problems caused by mutations in the small heat shock proteins HSPB1 and HSPB8. These mutations cause Charcot-Marie-Tooth disease (CMT) and distal hereditary neuropathies. These are both incurable, progressive disorders leading to severe motor and/or sensory problems. The aim of this project is the development of new cellular models and the creation of transgenic mouse models to get a better insight into the defects caused by mutant HSPB1 and HSPB8. In addition, these mouse models will offer the possibility to test new therapeutic strategies. With this research project, we would like to contribute to a better understanding of the pathogenesis of distal hereditary neuropathies and hopefully this will lead to a therapy for these incurable diseases.

Keywords:HSP27, HSPB1, Small heat shock protein, Axonal transport, Charcot-Marie-Tooth, Neurodegeneration

Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing