Publikationsserver der RWTH Aachen University
Charakterisierung der Auswirkungen einer pathogenen Mutation im Neurotrophinrezeptorgen trkA im Zellkulturmodell
Abstract
dc:descriptionThe development of the nervous system is a complex and highly regulated process in which the exact timing and location of the action of neurotrophins and their receptors plays an important role. They support survival and differentiation of neuronal cells. The prototypic neurotrophin NGF (nerve growth factor) specifically stimulates the transmembrane receptor TrkA. The TrkA Isoform II, which is expressed in neuronal cells only, can additionally be activated by Neurotrophin 3 (NT 3). TrkA knockout mice suffer from massive neuronal cell loss and most of them die within one month. In human patients mutations in the trkA gene can lead to hereditary sensory and autonomous neuropathy type IV (HSAN IV or CIPA = congenital insensitivity to pain with anhidrosis). This autosomal recessive disorder manifests in loss of pain and temperature sensitivity, the inability to sweat and often also mental retardation. Due to the human pathogenic mutation R780P close to the C terminus of TrkA and its phospholipaseCgamma (PLCgamma) binding site, the receptor cannot be phosphorylated anymore. In the present work it could be demonstrated that nevertheless downstream pathways could still be activated on a reduced level following stimulation with NGF and NT 3, respectively. Further analysis of the interaction with binding partners revealed that PLCgamma1 binding could still be detected but was compromised. However the interaction with Shc was unchanged compared to wild type TrkA receptor. In addition the R780P mutation led to alterations of intracellular TrkA trafficking. Following internalisation the receptor did not enter anymore the lysosomal degradative pathway, but – at least to some extent – was recycled back to the cell surface. Moreover, the mutation R780P led to defects in neurite outgrowth. These effects were accompanied by an impairment of protein stability of the mutated receptor and changes in the viability of transiently transfected cells. Hence a model is discussed in which the mutation R780P leads to the sorting of the receptor into recycling endosomes which allows a minimum of downstream pathway activation. Still, this activation is not sufficient to promote neurite outgrowth. These alterations could contribute to the pathomechanism leading to impaired innervation of sweat glands and skin in HSAN IV patients.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2010
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Flohr, Stefanie
- Contributors dc:contributor
-
- Weis, Joachim
Subjects
dc:subject × 20Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger