Studien zum endosomalen Transport und der Signaltransduktion des Nervenwachstumsfaktors NGF unter physiologischen und pathophysiologischen Bedingungen

Nerve growth factor and its receptors are essential for the nervous system. Their function depends on the spatial and temporal distribution within the cell. The neuro-trophic signal is transported in so called “signalling endosomes” which are retro-gradely transported over long distances from synapses to neuronal cell bodies. Sorting and transport defects severely impair the viability of neurons since the growth factors may need to bridge distances of one metre or more to travel from the location of activation to the cell bodies where they exert their function. Many neurodegenerative disorders show aspects of a disturbed vesicular transport and of ubiquitin-proteasome-system malfunction, demonstrated by the accumula-tion of ubiquitinated proteins within the affected neurons. Part one of this thesis aimed to elucidade whether the proteasome influences the function of the NGF receptor TrkA. Proteasomal inhibition led to an alteration of the endosomal trans-port of TrkA, switching from the lysosomal to the recycling pathway. This is accom-panied by a change in the phosphorylation status of TrkA and of the downstream signalling pathway of MAPK. Proteasomal inhibition leads to a NGF-dependent prolonged phosphorylation of TrkA and of the downstream effectors Erk1/2. The activity of Erk1/2 is spatially and temporally tightly regulated and appears to be de-pendent on the proteasome-regulated sorting of TrkA into the lysosomal pathway. Blocking proteasomal activity thus enhances the neuronal differentiation of PC12 cells. In the second part of the thesis the pH-dependent regulation of the affinity of the two NGF receptors to NGF was analyzed. The results presented herein provide evidence for a decreased affinity of TrkA to NGF at acidic endosomal pH values in comparison to neutral pH values representing the conditions on the surface of the cell. p75, on the other hand, appears to have a higher NGF affinity under low pH conditions. These findings emphazise the importance of the regulation of endosomal transport for TrkA function. The sorting to the individual endosomal compartments with their different pH values is apparently involved in the fine tuning of TrkA activity. One potential mechanism of this fine tuning is the pH-dependent regulation of the affinity of NGF to TrkA and p75.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2008

Author dc:creator

• Moises, Tina

Contributors dc:contributor

• Weis, Joachim

• info:eu-repo/classification/ddc/570
• Nervenwachstumsfaktor
• Nervendegeneration
• Protein-Tyrosin-Kinasen
• Endosom
• Signaltransduktion
• Protein-Protein-Wechselwirkung
• Biowissenschaften, Biologie
• TrkA
• endosomaler Transport
• NGF
• neurodegeneration
• endosomal trafficking
• protein-protein interaction

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113116%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A50576