Sangar, Daljit;
Hill, Elizabeth;
Jack, Kezia;
Batchelor, Mark;
Mistry, Beenaben;
Ribes, Juan M;
Jackson, Graham S;
... Bieschke, Jan; + view all
(2024)
Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates.
eLife
, 13
, Article e83320. 10.7554/eLife.83320.
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Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates.pdf - Published Version Download (4MB) | Preview |
Abstract
Prions replicate via the autocatalytic conversion of cellular prion protein (PrPC) into fibrillar assemblies of misfolded PrP. While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of fibril formation in vitro have precluded the identification and mechanistic analysis of cellular proteins, which may alter PrP self-assembly and prion replication. Here, we have developed a fibril formation assay for recombinant murine and human PrP (23-231) under near-native conditions (NAA) to study the effect of cellular proteins, which may be risk factors or potential therapeutic targets in prion disease. Genetic screening suggests that variants that increase syntaxin-6 expression in the brain (gene: STX6) are risk factors for sporadic Creutzfeldt–Jakob disease. Analysis of the protein in NAA revealed, counterintuitively, that syntaxin-6 is a potent inhibitor of PrP fibril formation. It significantly delayed the lag phase of fibril formation at highly sub-stoichiometric molar ratios. However, when assessing toxicity of different aggregation time points to primary neurons, syntaxin-6 prolonged the presence of neurotoxic PrP species. Electron microscopy and super-resolution fluorescence microscopy revealed that, instead of highly ordered fibrils, in the presence of syntaxin-6 PrP formed less-ordered aggregates containing syntaxin-6. These data strongly suggest that the protein can directly alter the initial phase of PrP self-assembly and, uniquely, can act as an ‘anti-chaperone’, which promotes toxic aggregation intermediates by inhibiting fibril formation.
| Type: | Article |
|---|---|
| Title: | Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7554/eLife.83320 |
| Publisher version: | https://doi.org/10.7554/eLife.83320 |
| Language: | English |
| Additional information: | Copyright Sangar et al. This article is distributed under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use and redistribution provided that the original author and source are credited. |
| 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10199258 |
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