NDLI: Amyloid Oligomers and Mature Fibrils Prepared from an Innocuous Protein Cause Diverging Cellular Death Mechanisms

Content Provider	Journal of Biological Chemistry (JBC)
Author	Harte, Níal P. Klyubin, Igor McCarthy, Eoin K. Min, Soyoung Garrahy, Sarah Ann Xie, Yongjing Davey, Gavin P. Boland, John J. Rowan, Michael J. Mok, K. Hun
Abstract	Despite significant advances, the molecular identity of the cytotoxic species populated during in vivo amyloid formation crucial for the understanding of neurodegenerative disorders is yet to be revealed. In this study lysozyme prefibrillar oligomers and fibrils in both mature and sonicated states have been isolated through an optimized ultrafiltration/ultracentrifugation method and characterized with various optical spectroscopic techniques, atomic force microscopy, and transmission electron microscopy. We examined their level and mode of toxicity on rat pheochromocytoma (PC12) cells in both differentiated and undifferentiated states. We find that oligomers and fibrils display cytotoxic capabilities toward cultured cells in vitro, with oligomers producing elevated levels of cellular injury toward undifferentiated PC12 cells (PC12undiff). Furthermore, dual flow cytometry staining experiments demonstrate that the oligomers and mature fibrils induce divergent cellular death pathways (apoptosis and secondary necrosis, respectively) in these PC12 cells. We have also shown that oligomers but not sonicated mature fibrils inhibit hippocampal long term potentiation, a form of synaptic plasticity implicated in learning and memory, in vivo. We conclude that our in vitro and in vivo findings confer a level of resistance toward amyloid fibrils, and that the PC 12-based comparative cytotoxicity assay can provide insights into toxicity differences between differently aggregated protein species.
Related Links	http://www.jbc.org/content/290/47/28343.abstract
Ending Page	28352
Starting Page	28343
Page Count	10
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	47
Volume Number	290
DOI	10.1074/jbc.M115.676072
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2015-11-20
Access Restriction	Open
Subject Keyword	Amyloid Apoptosis Cell death Fibril Neurodegenerative disease Oligomer Protein aggregation Protein misfolding Long term potentiation Neurobiology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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