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Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila

Catterson, James H; Minkley, Lucy; Aspe, Salomé; Judd-Mole, Sebastian; Moura, Sofia; Dyson, Miranda C; Rajasingam, Arjunan; ... Partridge, Linda; + view all (2023) Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila. Neurobiol Aging , 132 pp. 154-174. 10.1016/j.neurobiolaging.2023.09.008. Green open access

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Abstract

Amyloid β (Aβ) accumulation is a hallmark of Alzheimer's disease. In adult Drosophila brains, human Aβ overexpression harms climbing and lifespan. It's uncertain whether Aβ is intrinsically toxic or activates downstream neurodegeneration pathways. Our study uncovers a novel protective role against Aβ toxicity: intra-endoplasmic reticulum (ER) protein accumulation with a focus on laminin and collagen subunits. Despite high Aβ, laminin B1 (LanB1) overexpression robustly counters toxicity, suggesting a potential Aβ resistance mechanism. Other laminin subunits and collagen IV also alleviate Aβ toxicity; combining them with LanB1 augments the effect. Imaging reveals ER retention of LanB1 without altering Aβ secretion. LanB1's rescue function operates independently of the IRE1α/XBP1 ER stress response. ER-targeted GFP overexpression also mitigates Aβ toxicity, highlighting broader ER protein retention advantages. Proof-of-principle tests in murine hippocampal slices using mouse Lamb1 demonstrate ER retention in transduced cells, indicating a conserved mechanism. Though ER protein retention generally harms, it could paradoxically counter neuronal Aβ toxicity, offering a new therapeutic avenue for Alzheimer's disease.

Type: Article
Title: Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neurobiolaging.2023.09.008
Publisher version: https://doi.org/10.1016/j.neurobiolaging.2023.09.0...
Language: English
Additional information: © 2023 The Author(s). Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Alzheimer’s disease, Aβ toxicity, Drosophila melanogaster, ER retention, Endoplasmic reticulum, Laminin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10179111
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