Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila

Catterson, J. H. et al. (2023) Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila. Neurobiology of Aging, 132, pp. 154-174. (doi: 10.1016/j.neurobiolaging.2023.09.008) (PMID:37837732)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Woodling, Dr Nathan
• Authors: Catterson, J. H., Minkley, L., Aspe, S., Judd-Mole, S., Moura, S., Dyson, M. C., Rajasingam, A., Woodling, N. S., Atilano, M. L., Ahmad, M., Durrant, C. S., Spires-Jones, T. L., and Partridge, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Neurobiology of Aging
• Publisher: Elsevier BV
• ISSN: 0197-4580
• ISSN (Online): 1558-1497
• Published Online: 21 September 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Neurobiology of Aging 132:154-174
• Publisher Policy: Reproduced under a Creative Commons licence