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Title: Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture

Abstract

Recent studies suggest that soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of human wild type transthyretin (TTR) were produced to elucidate oligomer properties. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrene-labeled TTR, chemical cross-linking, and electron microscopy we demonstrated that early formed soluble oligomers (within minutes) from A-state TTR comprised on the average 20-30 TTR monomers. When administered to neuroblastoma cells these early oligomers proved highly cytotoxic and induced apoptosis after 48 h of incubation. More mature fibrils (>24 h of fibrillation) were non-toxic. Surprisingly, we also found that native tetrameric TTR, when purified and stored under cold conditions (4 deg. C) was highly cytotoxic. The effect could be partially restored by increasing the temperature of the protein. The cytotoxic effects of native tetrameric TTR likely stems from a hitherto unexplored low temperature induced rearrangement of the tetramer conformation that possibly is related to the conformation of misfolded TTR in amyloigogenic oligomers.

Authors:
;  [1];  [2];  [3];  [1]
  1. IFM- Department of Chemistry, Linkoeping University, SE-581 83 Linkoeping (Sweden)
  2. Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim (Norway)
  3. Division of Experimental Pathology, Faculty of Health Sciences, Linkoeping University, S-581 85 Linkoeping (Sweden)
Publication Date:
OSTI Identifier:
21255803
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 377; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2008.10.121; PII: S0006-291X(08)02081-0; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; ANISOTROPY; APOPTOSIS; CELL CULTURES; CROSS-LINKING; CYSTEINE; DISEASES; ELECTRON MICROSCOPY; FLUORESCENCE; MUTANTS; PATHOGENESIS; PROTEINS; PYRENE; TEMPERATURE RANGE 0065-0273 K; TEMPERATURE RANGE 0273-0400 K; TOXICITY

Citation Formats

Soergjerd, Karin, Klingstedt, Therese, Lindgren, Mikael, Kagedal, Katarina, and Hammarstroem, Per. Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture. United States: N. p., 2008. Web. doi:10.1016/j.bbrc.2008.10.121.
Soergjerd, Karin, Klingstedt, Therese, Lindgren, Mikael, Kagedal, Katarina, & Hammarstroem, Per. Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture. United States. https://doi.org/10.1016/j.bbrc.2008.10.121
Soergjerd, Karin, Klingstedt, Therese, Lindgren, Mikael, Kagedal, Katarina, and Hammarstroem, Per. 2008. "Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture". United States. https://doi.org/10.1016/j.bbrc.2008.10.121.
@article{osti_21255803,
title = {Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture},
author = {Soergjerd, Karin and Klingstedt, Therese and Lindgren, Mikael and Kagedal, Katarina and Hammarstroem, Per},
abstractNote = {Recent studies suggest that soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of human wild type transthyretin (TTR) were produced to elucidate oligomer properties. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrene-labeled TTR, chemical cross-linking, and electron microscopy we demonstrated that early formed soluble oligomers (within minutes) from A-state TTR comprised on the average 20-30 TTR monomers. When administered to neuroblastoma cells these early oligomers proved highly cytotoxic and induced apoptosis after 48 h of incubation. More mature fibrils (>24 h of fibrillation) were non-toxic. Surprisingly, we also found that native tetrameric TTR, when purified and stored under cold conditions (4 deg. C) was highly cytotoxic. The effect could be partially restored by increasing the temperature of the protein. The cytotoxic effects of native tetrameric TTR likely stems from a hitherto unexplored low temperature induced rearrangement of the tetramer conformation that possibly is related to the conformation of misfolded TTR in amyloigogenic oligomers.},
doi = {10.1016/j.bbrc.2008.10.121},
url = {https://www.osti.gov/biblio/21255803}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 377,
place = {United States},
year = {Fri Dec 26 00:00:00 EST 2008},
month = {Fri Dec 26 00:00:00 EST 2008}
}