Translational analysis of the mechanisms underlying small nerve fiber pathology in Fabry disease as a genetically determined model for neuropathic pain

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In this project we will investigate the pathophysiology of neuropathic pain using innovative and directly patient-associated methods. In the peripheral nervous system, nociception is transduced via thinly- and un-myelinated nerve fibers (A-delta and C). Pathophysiological alterations of these nociceptors by acquired or hereditary diseases may lead to neuropathic pain. Neuropathic pain is a cardinal symptom of Fabry disease, a X-chromosomally inherited disorder caused by mutations in the alpha-galactosidase A gene with consecutive lysosomal accumulation of the sphingolipid globotriaosylceramide 3 (Gb3). Based on our previous work we hypothesize that Gb3 interferes with the neuronal ion channel activity and that in parallel peripheral nociceptors are sensitized by inflammatory mediators secreted by surrounding cutaneous cells which together results in the typical neuropathic pain attacks in Fabry disease. We will test this hypothesis in a clinical-experimental approach using fibroblasts and keratinocytes obtained from skin punch biopsies of patients with Fabry disease and healthy controls. For the molecular, histological, and electrophysiological characterization of skin-nerve-neuron interactions we will generate two- and three-dimensional skin models from patient-derived fibroblasts and keratinocytes. These models will then be innervated with neuronal cells obtained from patients` fibroblasts via induced pluripotent stem cells. Data obtained from these completely patient-derived in vitro models will not only fundamentally improve our understanding of neuropathic pain pathophysiology in Fabry disease, but will also allow deciphering basic mechanisms of pain generation in other disorders. Furthermore, these model systems will open entirely novel possibilities for mechanism-based in vitro research including pharmacological testing of locally active potentially neuroprotective and analgesic compounds.