{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/399134"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/399134","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Regulation of autophagosome formation and maturation by neurodegeneration-associated proteins","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Palmer, Jennifer Eileen"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Rubinsztein, David"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-09-29","date_published":"2025-09-29","updated_at":"2026-07-22T22:24:03Z","subjects":["Autophagy","Neurodegeneration"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/b6df1056-d607-4a8a-b187-bdacbd6d3fae/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000178969135"],"render_values":[{"text":"0000-0001-7896-9135","href":"https://orcid.org/0000-0001-7896-9135","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.127784","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Rubinsztein, David"]},{"key":"dc:creator","label":"Author","values":["Palmer, Jennifer Eileen"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000178969135"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-09-29"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/399134"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Autophagy","Neurodegeneration"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/b6df1056-d607-4a8a-b187-bdacbd6d3fae/download","http://purl.org/NET/rdflicense/allrightsreserved"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2027-02-26"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.127784"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/b16bed28-190f-4458-82bf-e6f240a31705/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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. 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