Guha, IT; (2017) The importance of JNK in ageing nerve growth factor (NGF) - responsive neurons. Masters thesis , UCL (University College London).

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Abstract

In ageing, sub-populations of nerve growth factor (NGF)-responsive neurons are susceptible to neurodegeneration. Whereas aged sympathetic neurons lose their survival dependence on NGF, the NGF precursor, proNGF, has been found to be neurotoxic in these cells and this is mediated by p75-neurotrophin receptor (p75NTR) and sortilin. However, the intracellular pathway and mechanisms involved downstream require further investigation. As developing sympathetic neurons are NGF-dependent for survival, apoptosis has been observed in neonatal superior cervical ganglion (SCG), following NGF withdrawal, which is facilitated by p75NTR but attenuated by c-Jun N-terminal kinase (JNK) inhibition. The p75 neurotrophin receptor-interacting protein (NRAGE) has also been implicated in p75NTR-mediated cell death in NGF-responsive neurons. While plenty of research has focused on sympathetic neurons in development, this study sought to examine the effect of JNK and NRAGE inhibition in cultured SCG neurons and glia from aged and young adult mice. Through the use of pan-JNK inhibitors and AEG3482, which indirectly inhibits JNK via HSP90, the survival of young adult and aged NGF-treated cultured sympathetic neurons was found to be unaffected, but the formation of neurites and glial processes was restricted. Furthermore, using isoform-specific JNK inhibitors, results were consistent with JNK3 having a major role in this process. The survival and neurite outgrowth of NGF-treated cultured aged SCG neurons, subjected to siRNA knockdown of NRAGE, were both unaffected. Interestingly, both AEG3482 and NRAGE siRNA rescued the proNGF-mediated killing of aged SCG neurons. In addition, similar to NGF-treated cells, proNGF-mediated neurite outgrowth of aged SCG neurons was restricted during JNK inhibition but not following NRAGE knockdown in cell culture. In conclusion, while NRAGE is involved in proNGF-mediated neurotoxicity, JNK is required for both the proNGF-mediated cell death, and neuritogenesis, of SCG neurons and glia from aged mice and these findings have implications for therapeutic intervention.

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