Budzinska, Marta Izabela; (2019) Investigating the mechanisms regulating retrograde transport and signalling of neurotrophin receptors in neuronal cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Signalling by target-derived growth factors called neurotrophins (NT) is essential for the development of the nervous system and its maintenance throughout life. Neurons have very complex morphology, reaching up to a metre in length in humans, and strongly rely on fast axonal transport for the efficient delivery of biological molecules to ensure their homeostasis. It is therefore not surprising that perturbations connected to long-range trafficking and signalling are associated with neurological conditions. Although the transport of NT and their receptors (NTRs) is a well-characterized process, the molecular mechanism controlling the somatic sorting of activated NTRs towards a specific destination, such as recycling or degradation, is not completely understood. Recently, our laboratory demonstrated that the dynein motor adaptor, Bicaudal D1 (BICD1), is a main regulator of NTR sorting towards lysosomal degradation. Following the identification of protein tyrosine phosphatase, non-receptor type 23 (PTPN23) in the BICD1 interactome, I characterized their interaction using biochemical approaches and confocal microscopy. PTPN23 is a non-canonical member of the endosomal sorting complexes required for transport (ESCRT) family, which in non-neuronal cells mediates the turnover of transmembrane receptors, such as epidermal growth factor receptor (EGFR). By silencing PTPN23 expression and using an anti-NTR-antibody accumulation assay, I highlighted its novel role in NTR sorting in neuronal cells. The long-range trafficking machinery is also essential for effective responses to environmental insults, such as oxidative stress, which in healthy cells, including neurons, results in the formation of stress granules (SGs). In the second part of this project, I characterized BICD1 as a novel component of neuronal SGs, following a previous report identifying this molecule as a factor necessary for SG assembly. Furthermore, I demonstrated that oxidative stress decreases the sensitivity of neurons to NTs, revealed by the specific downregulation of NTR trafficking and signalling in response to BDNF stimulation.

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