Jakhria, T, Hellewell, AL, Porter, MY et al. (5 more authors) (2014) β2-microglobulin amyloid fibrils are nanoparticles that disrupt lysosomal membrane protein trafficking and inhibit protein degradation by lysosomes. Journal of Biological Chemistry, 289 (52). 35781 - 35794. ISSN 0021-9258
Abstract
Fragmentation of amyloid fibrils produces fibrils that are reduced in length but have an otherwise unchanged molecular architecture. The resultant nanoscale fibril particles inhibit the cellular reduction of the tetrazolium dye 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), a substrate commonly used to measure cell viability, to a greater extent than unfragmented fibrils. Here we show that the internalization of β2-microglobulin (β2m) amyloid fibrils is dependent on fibril length, with fragmented fibrils being more efficiently internalized by cells. Correspondingly, inhibiting the internalization of fragmented β2m fibrils rescued cellular MTT reduction. Incubation of cells with fragmented β2m fibrils did not, however, cause cell death. Instead, fragmented β2m fibrils accumulate in lysosomes, alter the trafficking of lysosomal membrane proteins, and inhibit the degradation of a model protein substrate by lysosomes. These findings suggest that nanoscale fibrils formed early during amyloid assembly reactions or by the fragmentation of longer fibrils could play a role in amyloid disease by disrupting protein degradation by lysosomes and trafficking in the endolysosomal pathway.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2014, Jakhria, T, Hellewell, AL, Porter, MY, Jackson, MP, Tipping, KW, Xue, WF, Radford, SE and Hewitt, EW. This is an Open Access article distributed in accordance with the Creative Commons Attribution (CC BY 3.0) licence, which permits others to distribute, remix, adapt, build upon this work, and license their derivative works on different terms, provided the original work is properly cited. |
Keywords: | Amyloid; fibril; lysosome; membrane trafficking; protein degradation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > NIHR Clinical Research Network Coordinating Centre (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Feb 2015 12:42 |
Last Modified: | 22 Apr 2015 14:46 |
Published Version: | http://dx.doi.org/10.1074/jbc.M114.586222 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology Inc. |
Identification Number: | 10.1074/jbc.M114.586222 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:83250 |