Regulation of autophagosome formation and maturation by neurodegeneration-associated proteins
type: CreativeWork
description: 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 releas…
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 releas…
author: Palmer, Jennifer Eileen
language: eng
keywords: Autophagy, Neurodegeneration
license: https://www.repository.cam.ac.uk/bitstreams/b6df1056-d607-4a8a-b187-bdacbd6d3fae/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-09-29
date modified: 2026-07-22T22:24:03Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.127784