Resistance of cell lines to prion toxicity aided by phospho-ERK expression

K M Uppington, D R Brown

Research output: Contribution to journalArticle

  • 18 Citations

Abstract

Prion diseases are fatal neurodegenerative disorders. They are characterised by neuronal loss and the accumulation of an abnormal protein in the CNS. Cell lines exist that express the toxic form of the prion protein (PrP) with little evidence of cell death. Other cell based models studying the mechanism by which cell death occurs employ exogenous application of peptides or fragments of PrP. In this study, we demonstrated that full-length recombinant PrP binding manganese was toxic to PrP-expressing cell lines and primary neuronal cultures but not to PrP-knockout neurones. This toxic form of PrP was also toxic to cell lines equivalently regardless of whether they were infected with scrapie or not. Both scrapie-infected cells and cells resistant to the toxicity of PrP showed increased levels of phosphorylated ERK protein. Scrapie-infected cells also showed elevated levels of caspase 12. Inhibition of phospho-ERK resulted in increased cell death suggesting the increased levels of phospho-ERK served a protective effect. These results suggest that scrapie-infected cell lines resist the toxicity of the prions they generate because they produce only low levels of abnormal protein and have increased resistance to apoptotic signs because of heightened activity of the MAP kinase pathway.
LanguageEnglish
Pages842-852
Number of pages11
JournalJournal of Neurochemistry
Volume105
Issue number3
DOIs
StatusPublished - May 2008

Fingerprint

Prions
Toxicity
Cells
Scrapie
Poisons
Cell Line
Cell death
Cell Death
Caspase 12
Peptide Fragments
Proteins
Prion Diseases
Manganese
Prion Proteins
Cell culture
Recombinant Proteins
Protein Binding
Neurodegenerative Diseases
Neurons
Phosphotransferases

Cite this

Resistance of cell lines to prion toxicity aided by phospho-ERK expression. / Uppington, K M; Brown, D R.

In: Journal of Neurochemistry, Vol. 105, No. 3, 05.2008, p. 842-852.

Research output: Contribution to journalArticle

@article{e174463aa5fc4bbfb7ed9d4f2c3955ca,
title = "Resistance of cell lines to prion toxicity aided by phospho-ERK expression",
abstract = "Prion diseases are fatal neurodegenerative disorders. They are characterised by neuronal loss and the accumulation of an abnormal protein in the CNS. Cell lines exist that express the toxic form of the prion protein (PrP) with little evidence of cell death. Other cell based models studying the mechanism by which cell death occurs employ exogenous application of peptides or fragments of PrP. In this study, we demonstrated that full-length recombinant PrP binding manganese was toxic to PrP-expressing cell lines and primary neuronal cultures but not to PrP-knockout neurones. This toxic form of PrP was also toxic to cell lines equivalently regardless of whether they were infected with scrapie or not. Both scrapie-infected cells and cells resistant to the toxicity of PrP showed increased levels of phosphorylated ERK protein. Scrapie-infected cells also showed elevated levels of caspase 12. Inhibition of phospho-ERK resulted in increased cell death suggesting the increased levels of phospho-ERK served a protective effect. These results suggest that scrapie-infected cell lines resist the toxicity of the prions they generate because they produce only low levels of abnormal protein and have increased resistance to apoptotic signs because of heightened activity of the MAP kinase pathway.",
author = "Uppington, {K M} and Brown, {D R}",
note = "ID number: ISI:000255139200024",
year = "2008",
month = "5",
doi = "10.1111/j.1471-4159.2007.05192.x",
language = "English",
volume = "105",
pages = "842--852",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Resistance of cell lines to prion toxicity aided by phospho-ERK expression

AU - Uppington,K M

AU - Brown,D R

N1 - ID number: ISI:000255139200024

PY - 2008/5

Y1 - 2008/5

N2 - Prion diseases are fatal neurodegenerative disorders. They are characterised by neuronal loss and the accumulation of an abnormal protein in the CNS. Cell lines exist that express the toxic form of the prion protein (PrP) with little evidence of cell death. Other cell based models studying the mechanism by which cell death occurs employ exogenous application of peptides or fragments of PrP. In this study, we demonstrated that full-length recombinant PrP binding manganese was toxic to PrP-expressing cell lines and primary neuronal cultures but not to PrP-knockout neurones. This toxic form of PrP was also toxic to cell lines equivalently regardless of whether they were infected with scrapie or not. Both scrapie-infected cells and cells resistant to the toxicity of PrP showed increased levels of phosphorylated ERK protein. Scrapie-infected cells also showed elevated levels of caspase 12. Inhibition of phospho-ERK resulted in increased cell death suggesting the increased levels of phospho-ERK served a protective effect. These results suggest that scrapie-infected cell lines resist the toxicity of the prions they generate because they produce only low levels of abnormal protein and have increased resistance to apoptotic signs because of heightened activity of the MAP kinase pathway.

AB - Prion diseases are fatal neurodegenerative disorders. They are characterised by neuronal loss and the accumulation of an abnormal protein in the CNS. Cell lines exist that express the toxic form of the prion protein (PrP) with little evidence of cell death. Other cell based models studying the mechanism by which cell death occurs employ exogenous application of peptides or fragments of PrP. In this study, we demonstrated that full-length recombinant PrP binding manganese was toxic to PrP-expressing cell lines and primary neuronal cultures but not to PrP-knockout neurones. This toxic form of PrP was also toxic to cell lines equivalently regardless of whether they were infected with scrapie or not. Both scrapie-infected cells and cells resistant to the toxicity of PrP showed increased levels of phosphorylated ERK protein. Scrapie-infected cells also showed elevated levels of caspase 12. Inhibition of phospho-ERK resulted in increased cell death suggesting the increased levels of phospho-ERK served a protective effect. These results suggest that scrapie-infected cell lines resist the toxicity of the prions they generate because they produce only low levels of abnormal protein and have increased resistance to apoptotic signs because of heightened activity of the MAP kinase pathway.

UR - http://www.scopus.com/inward/record.url?scp=42449102282&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1111/j.1471-4159.2007.05192.x

U2 - 10.1111/j.1471-4159.2007.05192.x

DO - 10.1111/j.1471-4159.2007.05192.x

M3 - Article

VL - 105

SP - 842

EP - 852

JO - Journal of Neurochemistry

T2 - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -