Endoplasmic Reticulum Morphoregulation Modulates Ca2+- Driven Brain Cell Functions
type: CreativeWork
description: Disruptions in the structural integrity of the Endoplasmic Reticulum (ER) have been associated with various neuronal pathologies, with mutations in some ER morphogens causing motor neurone diseases. The selective vulnerability of long axons highlights the significance of their extensive ER tubule-containing periphery for neuronal health, but the underlying pathophysiological mechanisms are yet to be elucidated. Therefore, a comprehensive investigation of the ER structure-function relationship is essential to better understand its role in disease progression. The ER forms an interconnected network of tubules that extend throughout the cell. One of the essential functions of the ER is to store large amounts of calcium (Ca2+ ) and sequester the ion on low-affinity/high-capacity protein carriers. This enables the ER to rapidly release Ca2+ in response to specific signals, either globally or locally. This led me to investigate how the tubular ER structure supports healthy Ca2+ handling. Utilising a toolkit tailored for ER manipulation, combined with live-cell imaging of ER luminal dynamics and Ca2+ fluxes, I demonstrate the intricate relationship between ER morphology and its Ca2+ supply capabilities. Data analyses are further enhanced by in silico physical modelling, with predictive power for fluid dynamics inside the lumen for various ER architectures. The model shows that mobile luminal Ca2+ -buffer proteins with moderate binding strength, moving through a well-connected network of tubules, are essential to achieve rapid Ca2+ release. The altered expression of ER morphogens disrupts the continuity and connectivity of the ER tubular network, thereby hindering transport through the ER, as indicated by the analysis of photoactivated protein spreading. Simulations and direct Ca2+ imaging demonstrate that such structural changes in the network limit Ca2+ supply to the point of demand, revealing a tunnelling mechanism by which the architecture of the tubular ER network modu…
abstract: Disruptions in the structural integrity of the Endoplasmic Reticulum (ER) have been associated with various neuronal pathologies, with mutations in some ER morphogens causing motor neurone diseases. The selective vulnerability of long axons highlights the significance of their extensive ER tubule-containing periphery for neuronal health, but the underlying pathophysiological mechanisms are yet to be elucidated. Therefore, a comprehensive investigation of the ER structure-function relationship is essential to better understand its role in disease progression. The ER forms an interconnected network of tubules that extend throughout the cell. One of the essential functions of the ER is to store large amounts of calcium (Ca2+ ) and sequester the ion on low-affinity/high-capacity protein carriers. This enables the ER to rapidly release Ca2+ in response to specific signals, either globally or locally. This led me to investigate how the tubular ER structure supports healthy Ca2+ handling. Utilising a toolkit tailored for ER manipulation, combined with live-cell imaging of ER luminal dynamics and Ca2+ fluxes, I demonstrate the intricate relationship between ER morphology and its Ca2+ supply capabilities. Data analyses are further enhanced by in silico physical modelling, with predictive power for fluid dynamics inside the lumen for various ER architectures. The model shows that mobile luminal Ca2+ -buffer proteins with moderate binding strength, moving through a well-connected network of tubules, are essential to achieve rapid Ca2+ release. The altered expression of ER morphogens disrupts the continuity and connectivity of the ER tubular network, thereby hindering transport through the ER, as indicated by the analysis of photoactivated protein spreading. Simulations and direct Ca2+ imaging demonstrate that such structural changes in the network limit Ca2+ supply to the point of demand, revealing a tunnelling mechanism by which the architecture of the tubular ER network modu…
author: Crapart, Cécile
language: eng
keywords: Astrocytes, Calcium imaging, Calcium signalling, Calcium tunnelling, Endoplasmic Reticulum, ER network architecture, ER–mitochondria interactions, In silico modelling, Live-cell microscopy, Neurodegeneration
license: https://www.repository.cam.ac.uk/bitstreams/9e0b1358-1f2f-49f0-9f2b-46107370c9f0/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-03-31
date modified: 2026-07-24T01:33:30Z
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.126267