Aβ toxicity rescued by protein retention in the ER
Aβ toxicity rescued by protein retention in the ER
Abstract Accumulation of Aβ in the brain is one of the hallmarks of Alzheimer’s disease (AD). In the adult Drosophila brain, human Aβ over-expression is toxic and leads to deterioration of climbing ability and shortened lifespan. However, it remains unknown if Aβ is inherently toxic or if it triggers toxic downstream pathways that lead to neurodegeneration. Here, we describe a novel, and previously unidentified, protective role of intracellular laminin chain accumulation. Despite high Aβ levels, over-expression of the extracellular matrix protein subunit Laminin B1 (LanB1) resulted in a robust rescue of toxicity, highlighting a potential protective mechanism of resistance to Aβ. Over-expression of other Laminin subunits and a Collagen IV subunit also significantly rescued Aβ toxicity, while combining LanB1 with these subunits led to an even larger rescue. Imaging revealed that LanB1 was retained in the ER but had no effect on the secretion of Aβ into the extracellular milieu. LanB1 rescued toxicity independently of the IRE1α/XBP1-mediated branch of the ER stress response. Interestingly, over-expression of ER-targeted GFP also rescued Aβ toxicity, indicating a potentially broader benefit of ER protein retention. Finally, in proof-of-principle lentiviral transduction experiments using murine organotypic hippocampal slice cultures, over-expression of mouse Lamb1 resulted in ER-retention in transduced cells, highlighting a conserved mechanism. Typically, retention of proteins in the ER is detrimental to cellular health, but in the context of neuronal Aβ toxicity it may prove to be beneficial and a new therapeutic avenue for AD.
Minkley Lucy、Aspe Salom¨|、Judd-Mole Sebastian、Woodling Nathaniel S、Ahmad Mumtaz、Catterson James H、Durrant Claire S、Dyson Miranda C、Spires-Jones Tara L、Rajasingam Arjunan、Partridge Linda、Moura Sofia、Atilano Magda L
Institute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin Building||Centre for Discovery Brain Sciences, UK Dementia Research Institute, The University of EdinburghCentre for Discovery Brain Sciences, UK Dementia Research Institute, The University of EdinburghInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingCentre for Discovery Brain Sciences, UK Dementia Research Institute, The University of EdinburghInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin Building||Max Planck Institute for Biology of AgeingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin BuildingInstitute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin Building
神经病学、精神病学基础医学分子生物学
Alzheimer’s diseaseLamininDrosophila melanogasterAβ toxicityextracellular matrixendoplasmic reticulumER stressneurodegenerationER retentionOrganotypic slice cultures
Minkley Lucy,Aspe Salom¨|,Judd-Mole Sebastian,Woodling Nathaniel S,Ahmad Mumtaz,Catterson James H,Durrant Claire S,Dyson Miranda C,Spires-Jones Tara L,Rajasingam Arjunan,Partridge Linda,Moura Sofia,Atilano Magda L.Aβ toxicity rescued by protein retention in the ER[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/2021.08.18.456775.点此复制
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