The strain-encoded relationship between PrPSc replication, stability and processing in neurons is predictive of the incubation period of disease

Jacob I. Ayers, Charles R. Schutt, Ronald A. Shikiya, Adriano Aguzzi, Anthony Kincaid, Jason C. Bartz

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrPSc, is an essential component of the infectious agent, the strain-specific relationship between PrPSc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrPSc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrPSc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrPSc amplification and higher PrPSc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrPSc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrPSc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrPSc in neurons.

Original languageEnglish
Article numbere1001317
JournalPLoS Pathogens
Volume7
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Neuroglia
Neurons
Prions
Carisoprodol
Microglia
Astrocytes
Cricetinae
Protein Isoforms
Prion Proteins

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

The strain-encoded relationship between PrPSc replication, stability and processing in neurons is predictive of the incubation period of disease. / Ayers, Jacob I.; Schutt, Charles R.; Shikiya, Ronald A.; Aguzzi, Adriano; Kincaid, Anthony; Bartz, Jason C.

In: PLoS Pathogens, Vol. 7, No. 3, e1001317, 03.2011.

Research output: Contribution to journalArticle

@article{d73e87b4344a47c08a046f2cbaf5df58,
title = "The strain-encoded relationship between PrPSc replication, stability and processing in neurons is predictive of the incubation period of disease",
abstract = "Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrPSc, is an essential component of the infectious agent, the strain-specific relationship between PrPSc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrPSc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrPSc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrPSc amplification and higher PrPSc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrPSc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrPSc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrPSc in neurons.",
author = "Ayers, {Jacob I.} and Schutt, {Charles R.} and Shikiya, {Ronald A.} and Adriano Aguzzi and Anthony Kincaid and Bartz, {Jason C.}",
year = "2011",
month = "3",
doi = "10.1371/journal.ppat.1001317",
language = "English",
volume = "7",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - The strain-encoded relationship between PrPSc replication, stability and processing in neurons is predictive of the incubation period of disease

AU - Ayers, Jacob I.

AU - Schutt, Charles R.

AU - Shikiya, Ronald A.

AU - Aguzzi, Adriano

AU - Kincaid, Anthony

AU - Bartz, Jason C.

PY - 2011/3

Y1 - 2011/3

N2 - Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrPSc, is an essential component of the infectious agent, the strain-specific relationship between PrPSc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrPSc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrPSc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrPSc amplification and higher PrPSc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrPSc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrPSc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrPSc in neurons.

AB - Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrPSc, is an essential component of the infectious agent, the strain-specific relationship between PrPSc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrPSc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrPSc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrPSc amplification and higher PrPSc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrPSc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrPSc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrPSc in neurons.

UR - http://www.scopus.com/inward/record.url?scp=79953286302&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953286302&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1001317

DO - 10.1371/journal.ppat.1001317

M3 - Article

VL - 7

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 3

M1 - e1001317

ER -