Cargando…

Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration

Prion diseases are characterized by accumulation of misfolded protein, gliosis, synaptic dysfunction, and ultimately neuronal loss. This sequence, mirroring key features of Alzheimer disease, is modeled well in ME7 prion disease. We used iTRAQ(TM)/mass spectrometry to compare the hippocampal proteom...

Descripción completa

Detalles Bibliográficos
Autores principales: Asuni, Ayodeji A., Gray, Bryony, Bailey, Joanne, Skipp, Paul, Perry, V. Hugh, O'Connor, Vincent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924314/
https://www.ncbi.nlm.nih.gov/pubmed/24366862
http://dx.doi.org/10.1074/jbc.M113.502690
_version_ 1782303724181389312
author Asuni, Ayodeji A.
Gray, Bryony
Bailey, Joanne
Skipp, Paul
Perry, V. Hugh
O'Connor, Vincent
author_facet Asuni, Ayodeji A.
Gray, Bryony
Bailey, Joanne
Skipp, Paul
Perry, V. Hugh
O'Connor, Vincent
author_sort Asuni, Ayodeji A.
collection PubMed
description Prion diseases are characterized by accumulation of misfolded protein, gliosis, synaptic dysfunction, and ultimately neuronal loss. This sequence, mirroring key features of Alzheimer disease, is modeled well in ME7 prion disease. We used iTRAQ(TM)/mass spectrometry to compare the hippocampal proteome in control and late-stage ME7 animals. The observed changes associated with reactive glia highlighted some specific proteins that dominate the proteome in late-stage disease. Four of the up-regulated proteins (GFAP, high affinity glutamate transporter (EAAT-2), apo-J (Clusterin), and peroxiredoxin-6) are selectively expressed in astrocytes, but astrocyte proliferation does not contribute to their up-regulation. The known functional role of these proteins suggests this response acts against protein misfolding, excitotoxicity, and neurotoxic reactive oxygen species. A recent convergence of genome-wide association studies and the peripheral measurement of circulating levels of acute phase proteins have focused attention on Clusterin as a modifier of late-stage Alzheimer disease and a biomarker for advanced neurodegeneration. Since ME7 animals allow independent measurement of acute phase proteins in the brain and circulation, we extended our investigation to address whether changes in the brain proteome are detectable in blood. We found no difference in the circulating levels of Clusterin in late-stage prion disease when animals will show behavioral decline, accumulation of misfolded protein, and dramatic synaptic and neuronal loss. This does not preclude an important role of Clusterin in late-stage disease, but it cautions against the assumption that brain levels provide a surrogate peripheral measure for the progression of brain degeneration.
format Online
Article
Text
id pubmed-3924314
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-39243142014-02-14 Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration Asuni, Ayodeji A. Gray, Bryony Bailey, Joanne Skipp, Paul Perry, V. Hugh O'Connor, Vincent J Biol Chem Neurobiology Prion diseases are characterized by accumulation of misfolded protein, gliosis, synaptic dysfunction, and ultimately neuronal loss. This sequence, mirroring key features of Alzheimer disease, is modeled well in ME7 prion disease. We used iTRAQ(TM)/mass spectrometry to compare the hippocampal proteome in control and late-stage ME7 animals. The observed changes associated with reactive glia highlighted some specific proteins that dominate the proteome in late-stage disease. Four of the up-regulated proteins (GFAP, high affinity glutamate transporter (EAAT-2), apo-J (Clusterin), and peroxiredoxin-6) are selectively expressed in astrocytes, but astrocyte proliferation does not contribute to their up-regulation. The known functional role of these proteins suggests this response acts against protein misfolding, excitotoxicity, and neurotoxic reactive oxygen species. A recent convergence of genome-wide association studies and the peripheral measurement of circulating levels of acute phase proteins have focused attention on Clusterin as a modifier of late-stage Alzheimer disease and a biomarker for advanced neurodegeneration. Since ME7 animals allow independent measurement of acute phase proteins in the brain and circulation, we extended our investigation to address whether changes in the brain proteome are detectable in blood. We found no difference in the circulating levels of Clusterin in late-stage prion disease when animals will show behavioral decline, accumulation of misfolded protein, and dramatic synaptic and neuronal loss. This does not preclude an important role of Clusterin in late-stage disease, but it cautions against the assumption that brain levels provide a surrogate peripheral measure for the progression of brain degeneration. American Society for Biochemistry and Molecular Biology 2014-02-14 2013-12-23 /pmc/articles/PMC3924314/ /pubmed/24366862 http://dx.doi.org/10.1074/jbc.M113.502690 Text en © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Neurobiology
Asuni, Ayodeji A.
Gray, Bryony
Bailey, Joanne
Skipp, Paul
Perry, V. Hugh
O'Connor, Vincent
Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration
title Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration
title_full Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration
title_fullStr Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration
title_full_unstemmed Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration
title_short Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration
title_sort analysis of the hippocampal proteome in me7 prion disease reveals a predominant astrocytic signature and highlights the brain-restricted production of clusterin in chronic neurodegeneration
topic Neurobiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924314/
https://www.ncbi.nlm.nih.gov/pubmed/24366862
http://dx.doi.org/10.1074/jbc.M113.502690
work_keys_str_mv AT asuniayodejia analysisofthehippocampalproteomeinme7priondiseaserevealsapredominantastrocyticsignatureandhighlightsthebrainrestrictedproductionofclusterininchronicneurodegeneration
AT graybryony analysisofthehippocampalproteomeinme7priondiseaserevealsapredominantastrocyticsignatureandhighlightsthebrainrestrictedproductionofclusterininchronicneurodegeneration
AT baileyjoanne analysisofthehippocampalproteomeinme7priondiseaserevealsapredominantastrocyticsignatureandhighlightsthebrainrestrictedproductionofclusterininchronicneurodegeneration
AT skipppaul analysisofthehippocampalproteomeinme7priondiseaserevealsapredominantastrocyticsignatureandhighlightsthebrainrestrictedproductionofclusterininchronicneurodegeneration
AT perryvhugh analysisofthehippocampalproteomeinme7priondiseaserevealsapredominantastrocyticsignatureandhighlightsthebrainrestrictedproductionofclusterininchronicneurodegeneration
AT oconnorvincent analysisofthehippocampalproteomeinme7priondiseaserevealsapredominantastrocyticsignatureandhighlightsthebrainrestrictedproductionofclusterininchronicneurodegeneration