Lloyd, Emma; (2025) Biogenic activity of peripheral sensory nerves during homeostasis and regeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Peripheral nerves (PNs) are quiescent throughout adulthood yet retain the plasticity that allows them to regenerate following injury. Unlike many tissues, PNs lack a resident stem cell pool, comprising predominantly of postmitotic or quiescent cells, including neurons and glia. In the steady state these long-lived cells do not divide, and so, homeostasis is regulated primarily at the single cell level, requiring each cell to retain its size, structure, and function throughout adulthood. However, the mechanisms enabling the maintenance of this robust homeostatic state while retaining the plasticity required to re-enter a growth conducive state are not fully understood. To determine how cellular biogenesis levels contribute towards the maintenance of the quiescent state, and the switch towards a regenerative state, we conducted a comprehensive analysis of the biogenic activity of cell types found along the length of adult PNs. To do this, we focused on dorsal root ganglia, the nerve trunk, and cutaneous terminal nerve endings. Using assays to detect nascent RNA and protein synthesis, indicative of total biogenic rates, we showed that cell types within PN compartments have distinct mechanisms to control biogenesis in the adult steady state, as well as different responses following injury. In parallel, we investigated the role of localised protein biogenesis in adult sensory neurons in vitro and found a specific, spatial regulation of protein synthesis in the growth cones and axons following depolarisation and neurotrophic stimulation, showing that local protein synthesis occurs in a pseudo-steady state model of adult sensory neurons. Together, this work provides insight into the regulation of homeostasis in the PN, demonstrating that RNA and protein biogenesis are modulated in a cell-type specific manner. Overall, these differences in biogenesis could reflect neuron specific vulnerabilities and susceptibility towards neurodegenerative disease and PN pathologies.

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