Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro

Linda Alice Bergstrøm, Henriette Cordes Hvass, N. Zsurger, Peter M. H. Heegaard, H. Laursen, J. Chabry

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrPSc) of the cellular prion protein (PrPC) primarily in the central nervous system. The synthetic prion peptide PrP106-126 shares many characteristics with PrPSc in that it shows PrPC-dependent neurotoxicity both in vivo and in vitro. Moreover, PrP106-126 in vitro neurotoxicity has been closely associated with the ability to form fibrils. Here, we studied the in vivo neurotoxicity of molecular variants of PrP106-126 toward retinal neurons using electroretinographic recordings in mice after intraocular injections of the peptides. We found that amidation and structure relaxation of PrP106-126 significantly reduced the neurotoxicity in vivo. This was also found in vitro in primary neuronal cultures from mouse and rat brain. Thioflavin T binding studies showed that amidation and structure relaxation significantly reduced the ability of PrP106-126 to attain fibrillar structures in physiological salt solutions. This study hence supports the assumption that the neurotoxic potential of PrP106-126 is closely related to its ability to attain secondary structure.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume280
Issue number24
Pages (from-to)23114-23121
ISSN0021-9258
DOIs
Publication statusPublished - 2005

Cite this

Bergstrøm, Linda Alice ; Hvass, Henriette Cordes ; Zsurger, N. ; Heegaard, Peter M. H. ; Laursen, H. ; Chabry, J. / Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 24. pp. 23114-23121.
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title = "Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro",
abstract = "One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrPSc) of the cellular prion protein (PrPC) primarily in the central nervous system. The synthetic prion peptide PrP106-126 shares many characteristics with PrPSc in that it shows PrPC-dependent neurotoxicity both in vivo and in vitro. Moreover, PrP106-126 in vitro neurotoxicity has been closely associated with the ability to form fibrils. Here, we studied the in vivo neurotoxicity of molecular variants of PrP106-126 toward retinal neurons using electroretinographic recordings in mice after intraocular injections of the peptides. We found that amidation and structure relaxation of PrP106-126 significantly reduced the neurotoxicity in vivo. This was also found in vitro in primary neuronal cultures from mouse and rat brain. Thioflavin T binding studies showed that amidation and structure relaxation significantly reduced the ability of PrP106-126 to attain fibrillar structures in physiological salt solutions. This study hence supports the assumption that the neurotoxic potential of PrP106-126 is closely related to its ability to attain secondary structure.",
author = "Bergstr{\o}m, {Linda Alice} and Hvass, {Henriette Cordes} and N. Zsurger and Heegaard, {Peter M. H.} and H. Laursen and J. Chabry",
year = "2005",
doi = "10.1074/jbc.M500210200",
language = "English",
volume = "280",
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journal = "Journal of Biological Chemistry",
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Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro. / Bergstrøm, Linda Alice; Hvass, Henriette Cordes; Zsurger, N.; Heegaard, Peter M. H.; Laursen, H.; Chabry, J.

In: Journal of Biological Chemistry, Vol. 280, No. 24, 2005, p. 23114-23121.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro

AU - Bergstrøm, Linda Alice

AU - Hvass, Henriette Cordes

AU - Zsurger, N.

AU - Heegaard, Peter M. H.

AU - Laursen, H.

AU - Chabry, J.

PY - 2005

Y1 - 2005

N2 - One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrPSc) of the cellular prion protein (PrPC) primarily in the central nervous system. The synthetic prion peptide PrP106-126 shares many characteristics with PrPSc in that it shows PrPC-dependent neurotoxicity both in vivo and in vitro. Moreover, PrP106-126 in vitro neurotoxicity has been closely associated with the ability to form fibrils. Here, we studied the in vivo neurotoxicity of molecular variants of PrP106-126 toward retinal neurons using electroretinographic recordings in mice after intraocular injections of the peptides. We found that amidation and structure relaxation of PrP106-126 significantly reduced the neurotoxicity in vivo. This was also found in vitro in primary neuronal cultures from mouse and rat brain. Thioflavin T binding studies showed that amidation and structure relaxation significantly reduced the ability of PrP106-126 to attain fibrillar structures in physiological salt solutions. This study hence supports the assumption that the neurotoxic potential of PrP106-126 is closely related to its ability to attain secondary structure.

AB - One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrPSc) of the cellular prion protein (PrPC) primarily in the central nervous system. The synthetic prion peptide PrP106-126 shares many characteristics with PrPSc in that it shows PrPC-dependent neurotoxicity both in vivo and in vitro. Moreover, PrP106-126 in vitro neurotoxicity has been closely associated with the ability to form fibrils. Here, we studied the in vivo neurotoxicity of molecular variants of PrP106-126 toward retinal neurons using electroretinographic recordings in mice after intraocular injections of the peptides. We found that amidation and structure relaxation of PrP106-126 significantly reduced the neurotoxicity in vivo. This was also found in vitro in primary neuronal cultures from mouse and rat brain. Thioflavin T binding studies showed that amidation and structure relaxation significantly reduced the ability of PrP106-126 to attain fibrillar structures in physiological salt solutions. This study hence supports the assumption that the neurotoxic potential of PrP106-126 is closely related to its ability to attain secondary structure.

U2 - 10.1074/jbc.M500210200

DO - 10.1074/jbc.M500210200

M3 - Journal article

VL - 280

SP - 23114

EP - 23121

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 24

ER -