Cell invasive amyloid assemblies from SARS-CoV-2 peptides can form multiple polymorphs with varying neurotoxicity.

Autor:	Sanislav O; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria 3086, Australia., Tetaj R; Institute for Chemistry and Bioanalytics, School of Life Sciences, FHNW, Muttenz, 4132, Switzerland.; Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia. nicholas.reynolds@latrobe.edu.au., Metali; Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia. nicholas.reynolds@latrobe.edu.au., Ratcliffe J; Bio Imaging Platform, La Trobe University, Melbourne, Victoria 3086, Australia., Phillips W; Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia. nicholas.reynolds@latrobe.edu.au., Klein AR; Australian Nuclear Science and Technology Organisation (ANSTO), Australian Synchrotron, Clayton, Victoria 3168, Australia., Sethi A; Australian Nuclear Science and Technology Organisation (ANSTO), Australian Synchrotron, Clayton, Victoria 3168, Australia., Zhou J; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, LFO, E23, 8092, Zurich, Switzerland., Mezzenga R; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, LFO, E23, 8092, Zurich, Switzerland.; Department of Materials, ETH Zurich, Zurich, 8093, Switzerland., Saxer SS; Institute for Chemistry and Bioanalytics, School of Life Sciences, FHNW, Muttenz, 4132, Switzerland., Charnley M; Optical Sciences Centre, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.; Immune Signalling Laboratory, Peter MacCallum Cancer Centre, Parkville, Victoria 3000, Australia., Annesley SJ; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria 3086, Australia., Reynolds NP; Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia. nicholas.reynolds@latrobe.edu.au.; The Biomedical and Environmental Sensor Technology (BEST) Research Centre, Biosensors Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Victoria 3086, Australia.
Jazyk:	angličtina
Zdroj:	Nanoscale [Nanoscale] 2024 Oct 31; Vol. 16 (42), pp. 19814-19827. Date of Electronic Publication: 2024 Oct 31.
DOI:	10.1039/d4nr03030c
Abstrakt:	The neurological symptoms of COVID-19, often referred to as neuro-COVID include neurological pain, memory loss, cognitive and sensory disruption. These neurological symptoms can persist for months and are known as Post-Acute Sequalae of COVID-19 (PASC). The molecular origins of neuro-COVID, and how it contributes to PASC are unknown, however a growing body of research highlights that the self-assembly of protein fragments from SARS-CoV-2 into amyloid nanofibrils may play a causative role. Previously, we identified two fragments from the SARS-CoV-2 proteins, Open Reading Frame (ORF) 6 and ORF10, that self-assemble into neurotoxic amyloid assemblies. Here we further our understanding of the self-assembly mechanisms and nano-architectures formed by these fragments and their biological responses. By solubilising the peptides in a fluorinated solvent, we eliminate insoluble aggregates in the starting materials (seeds) that change the polymorphic landscape of the assemblies. The resultant assemblies are dominated by structures with higher free energies ( e.g. ribbons and amorphous aggregates) that are less toxic to cultured neurons but do affect their mitochondrial respiration. We also show the first direct evidence of cellular uptake of viral amyloids. This work highlights the importance of understanding the polymorphic behaviour of amyloids and the correlation to neurotoxicity, particularly in the context of neuro-COVID and PASC.
Databáze:	MEDLINE
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