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Regulation of autophagosome formation and maturation by neurodegeneration-associated proteins https://doi.org/10.17863/CAM.127784 Palmer, Jennifer Eileen 0000000178969135 Rubinsztein, David Autophagy is a cellular clearance pathway that maintains homeostasis by degrading and recycling superfluous, toxic, or damaged cellular components, including the aggregation-prone proteins and dysfunctional organelles associated with neurodegenerative diseases. Autophagy cargoes are captured into double-membraned autophagosomes, which form as outgrowths from the Ras-related protein 11A (RAB11A)-positive recycling endosomes. Autophagosomes are closed by the endosomal sorting complex required for transport (ESCRT) complex and then released by dynamin 2 (DNM2) before fusing with lysosomes to enable the degradation of the autophagy substrates. Impaired autophagic clearance is a shared hallmark of neurodegenerative diseases and exacerbates neurodegeneration. I aimed to investigate how particular neurodegeneration-associated proteins affect autophagy, which contributes to our understanding of the pathological processes of neurodegenerative diseases and can potentially identify novel physiological mechanisms of autophagy regulation. I discovered that the Alzheimer’s disease (AD)-associated protein Myc box-dependent interacting protein 1 (BIN1) negatively regulates autophagosome maturation by inhibiting the DNM2-dependent release of nascent autophagosomes from the recycling endosomes. Genetic polymorphisms that increase the expression of BIN1 specifically in microglia increase the risk of developing AD. I showed that the overexpression of BIN1, including in microglia, impairs autophagic clearance. As impaired microglial autophagy has been linked to altered microglial functions and exacerbated neurodegeneration, this provides a possible mechanism for how the BIN1 variants increase the risk of AD. I also discovered a novel physiological role for BIN1 in the coordination of ESCRT-dependent autophagosome closure and DNM2-dependent autophagosome release from the recycling endosomes. BIN1 interacts with the ESCRT-III complex at phagophores and inhibits DNM2, preventing the release of open phagophores. Autophagosome closure and dissociation of the ESCRT-III complex releases BIN1, removing the inhibition of DNM2 and allowing the closed autophagosomes to be released. Additionally, I investigated whether the altered trafficking of RAB11A-positive recycling endosomes, a process linked to the Huntington’s disease (HD)-associated protein Huntingtin (HTT), affects autophagy. Through a variety of approaches to manipulate the trafficking of RAB11A, I discovered that the alteration of the normal movement of RAB11A-positive recycling endosomes impairs autophagosome formation. This research has potential implications for the development of HTT-targeting genetic therapies for HD. These studies identify novel mechanisms of autophagy regulation and how autophagy is impaired by AD- and HD-associated proteins, guiding the future development and application of potential disease-modifying therapies for neurodegenerative diseases. University of Cambridge 2025-09-29 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/399134 embargo 2027-02-26 https://www.repository.cam.ac.uk/bitstreams/b16bed28-190f-4458-82bf-e6f240a31705/download c2a8ec7f24ef30ea70e5b589195312ff https://www.repository.cam.ac.uk/bitstreams/b6df1056-d607-4a8a-b187-bdacbd6d3fae/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved Autophagy Neurodegeneration