Manferrari, Giulia; (2024) Molecular insights into motor neuron development and glial function: capturing the RNA interactomes of SFPQ and TDP-43. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The study of RNA-binding protein (RBP) interactions with RNA is crucial for our understanding of a plethora of cellular functions and regulatory mechanisms. Improved individual nucleotide Cross-Linking Immunoprecipitation (iiCLIP) technology can resolve with high specificity and precision RBP-RNA interactions, offering in-depth insights into RBPs molecular dynamics. In my thesis, I used iiCLIP to investigate SFPQ and TDP-43 interactions with target RNAs in cell specific contexts. Firstly, I investigate SFPQ-RNA interaction during motor neuron (MN) development. SFPQ is a key player in neuronal development, although its regulatory role in RNA processes and metabolism has been poorly explored in the context of MNs development. By investigating its RNA interactions over the course of neurogenesis, this research sheds light on the molecular roles of SFPQ in the orchestration of motor neuron differentiation and maturation. The second part of my thesis focuses on TDP-43-RNA interaction in astrocytes, exploring its role in maintaining astrocyte homeostasis and response to reactivity under different stimuli. TDP-43, implicated in various neurodegenerative disorders across multiple cell types, can expand our understanding of astrocyte function under physiological and pathological conditions. This study dissects the mechanisms by which TDP-43 influences astrocyte reactivity, contributing to the broader understanding of the role of this RBP in glial cell biology and its implications in glial and neuronal health. Through the lens of iiCLIP analysis, this thesis explores the specific roles of TDP-43 and SFPQ in different cellular types, developmental stages and activation states, uncovering the critical impact of RBP-RNA interactions in the regulation of their transcriptional landscape.

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