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Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology

BACKGROUND: Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic featur...

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Autores principales: Pace, Michael C., Xu, Guilian, Fromholt, Susan, Howard, John, Giasson, Benoit I., Lewis, Jada, Borchelt, David R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960184/
https://www.ncbi.nlm.nih.gov/pubmed/29776378
http://dx.doi.org/10.1186/s13024-018-0253-9
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author Pace, Michael C.
Xu, Guilian
Fromholt, Susan
Howard, John
Giasson, Benoit I.
Lewis, Jada
Borchelt, David R.
author_facet Pace, Michael C.
Xu, Guilian
Fromholt, Susan
Howard, John
Giasson, Benoit I.
Lewis, Jada
Borchelt, David R.
author_sort Pace, Michael C.
collection PubMed
description BACKGROUND: Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS: Mice expressing high levels of mutant forms of tau and α-synuclein (αSyn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation. RESULTS: Mice expressing low levels of G85R-SOD1:YFP, alone, lived normal lifespans and were free of evidence of inclusion pathology, setting the stage to use this protein as a reporter of proteostatic function. We observed robust induction of G85R-SOD1:YFP inclusion pathology in the neuropil of spinal cord and brainstem of bigenic mice that co-express high levels of mutant tau in the spinal axis and develop robust spinal tau pathology (JNPL3 mice). In contrast, in crosses of the G85R-SOD1:YFP mice with mice that model spinal α-synucleinopathy (the M83 model of αSyn pathology), we observed no G85R-SOD1:YFP inclusion formation. Similarly, in crosses of the G85R-SOD1:YFP mice to mice that model cortical tau pathology (rTg4510 mice), we did not observe induction of G85R-SOD1:YFP inclusions. CONCLUSION: Despite robust burdens of neurodegenerative pathology in M83 and rTg4510 mice, the introduction of the G85R-SOD1:YFP protein was induced to aggregate only in the context of spinal tau pathology present in the JNPL3 model. These findings suggest unexpected specificity, mediated by both the primary protein pathology and cellular context, in the induced “secondary aggregation” of a mutant form of SOD1 that could be viewed as a reporter of proteostatic function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0253-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-59601842018-05-24 Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology Pace, Michael C. Xu, Guilian Fromholt, Susan Howard, John Giasson, Benoit I. Lewis, Jada Borchelt, David R. Mol Neurodegener Research Article BACKGROUND: Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS: Mice expressing high levels of mutant forms of tau and α-synuclein (αSyn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation. RESULTS: Mice expressing low levels of G85R-SOD1:YFP, alone, lived normal lifespans and were free of evidence of inclusion pathology, setting the stage to use this protein as a reporter of proteostatic function. We observed robust induction of G85R-SOD1:YFP inclusion pathology in the neuropil of spinal cord and brainstem of bigenic mice that co-express high levels of mutant tau in the spinal axis and develop robust spinal tau pathology (JNPL3 mice). In contrast, in crosses of the G85R-SOD1:YFP mice with mice that model spinal α-synucleinopathy (the M83 model of αSyn pathology), we observed no G85R-SOD1:YFP inclusion formation. Similarly, in crosses of the G85R-SOD1:YFP mice to mice that model cortical tau pathology (rTg4510 mice), we did not observe induction of G85R-SOD1:YFP inclusions. CONCLUSION: Despite robust burdens of neurodegenerative pathology in M83 and rTg4510 mice, the introduction of the G85R-SOD1:YFP protein was induced to aggregate only in the context of spinal tau pathology present in the JNPL3 model. These findings suggest unexpected specificity, mediated by both the primary protein pathology and cellular context, in the induced “secondary aggregation” of a mutant form of SOD1 that could be viewed as a reporter of proteostatic function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0253-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-18 /pmc/articles/PMC5960184/ /pubmed/29776378 http://dx.doi.org/10.1186/s13024-018-0253-9 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Pace, Michael C.
Xu, Guilian
Fromholt, Susan
Howard, John
Giasson, Benoit I.
Lewis, Jada
Borchelt, David R.
Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
title Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
title_full Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
title_fullStr Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
title_full_unstemmed Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
title_short Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology
title_sort differential induction of mutant sod1 misfolding and aggregation by tau and α-synuclein pathology
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960184/
https://www.ncbi.nlm.nih.gov/pubmed/29776378
http://dx.doi.org/10.1186/s13024-018-0253-9
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