Hewlett, Bailey; (2025) Determining the Essential Roles of IRE1 Membrane Stress Responses upon Disruptions in Inter-Organelle Contacts. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Disruptions in inter-organelle contacts result in defects in membrane lipid and calcium homeostasis and are linked to the progression of several neurodegenerative diseases. Yet, our knowledge of mechanisms for sensing and responding to membrane stress remains incomplete. My research studies employ yeast and animal systems to understand how alterations in inter-organelle contacts impact membrane lipid homeostasis and stress responses. The results show that Ire1-dependent membrane stress responses (MSR), distinct from the classical unfolded protein response (UPR), are sufficient for growth of yeast cells lacking inter-organelle contact proteins. Quantitative lipidomics and imaging analyses further reveal that Ire1 modulates calcium dynamics and Orm1/2 protein levels to maintain sphingolipid homeostasis upon loss of inter-organelle contacts. Furthermore, my data show that a dominant negative form of the inter-organelle tether protein VAP-B, that is linked to a familial form of Amyotrophic Lateral Sclerosis (ALS8), not only impacts membrane lipid homeostasis but also impairs the IRE1-mediated MSR in mammalian cells. Importantly, small molecule compounds that induce IRE1 activity rescue cellular degeneration in a Drosophila model of ALS8. Altogether, these findings suggest that targeting IRE1-mediated MSR may be beneficial in preventing motor neuron degeneration during the progression of ALS8.

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