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.
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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 |
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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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