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Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo

Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, t...

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Autores principales: Llavero Hurtado, Maica, Fuller, Heidi R., Wong, Andrew M. S., Eaton, Samantha L., Gillingwater, Thomas H., Pennetta, Giuseppa, Cooper, Jonathan D., Wishart, Thomas M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622084/
https://www.ncbi.nlm.nih.gov/pubmed/28963550
http://dx.doi.org/10.1038/s41598-017-12603-0
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author Llavero Hurtado, Maica
Fuller, Heidi R.
Wong, Andrew M. S.
Eaton, Samantha L.
Gillingwater, Thomas H.
Pennetta, Giuseppa
Cooper, Jonathan D.
Wishart, Thomas M.
author_facet Llavero Hurtado, Maica
Fuller, Heidi R.
Wong, Andrew M. S.
Eaton, Samantha L.
Gillingwater, Thomas H.
Pennetta, Giuseppa
Cooper, Jonathan D.
Wishart, Thomas M.
author_sort Llavero Hurtado, Maica
collection PubMed
description Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, the reasons why synapses are particularly vulnerable to such a broad range of neurodegeneration inducing stimuli remains unknown. To identify molecular modulators of synaptic stability and degeneration, we have used the Cln3 (−/−) mouse model of a juvenile form of NCL. We profiled and compared the molecular composition of anatomically-distinct, differentially-affected pre-synaptic populations from the Cln3 (−/−) mouse brain using proteomics followed by bioinformatic analyses. Identified protein candidates were then tested using a Drosophila CLN3 model to study their ability to modify the CLN3-neurodegenerative phenotype in vivo. We identified differential perturbations in a range of molecular cascades correlating with synaptic vulnerability, including valine catabolism and rho signalling pathways. Genetic and pharmacological targeting of key ‘hub’ proteins in such pathways was sufficient to modulate phenotypic presentation in a Drosophila CLN3 model. We propose that such a workflow provides a target rich method for the identification of novel disease regulators which could be applicable to the study of other conditions where appropriate models exist.
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spelling pubmed-56220842017-10-12 Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo Llavero Hurtado, Maica Fuller, Heidi R. Wong, Andrew M. S. Eaton, Samantha L. Gillingwater, Thomas H. Pennetta, Giuseppa Cooper, Jonathan D. Wishart, Thomas M. Sci Rep Article Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, the reasons why synapses are particularly vulnerable to such a broad range of neurodegeneration inducing stimuli remains unknown. To identify molecular modulators of synaptic stability and degeneration, we have used the Cln3 (−/−) mouse model of a juvenile form of NCL. We profiled and compared the molecular composition of anatomically-distinct, differentially-affected pre-synaptic populations from the Cln3 (−/−) mouse brain using proteomics followed by bioinformatic analyses. Identified protein candidates were then tested using a Drosophila CLN3 model to study their ability to modify the CLN3-neurodegenerative phenotype in vivo. We identified differential perturbations in a range of molecular cascades correlating with synaptic vulnerability, including valine catabolism and rho signalling pathways. Genetic and pharmacological targeting of key ‘hub’ proteins in such pathways was sufficient to modulate phenotypic presentation in a Drosophila CLN3 model. We propose that such a workflow provides a target rich method for the identification of novel disease regulators which could be applicable to the study of other conditions where appropriate models exist. Nature Publishing Group UK 2017-09-29 /pmc/articles/PMC5622084/ /pubmed/28963550 http://dx.doi.org/10.1038/s41598-017-12603-0 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Llavero Hurtado, Maica
Fuller, Heidi R.
Wong, Andrew M. S.
Eaton, Samantha L.
Gillingwater, Thomas H.
Pennetta, Giuseppa
Cooper, Jonathan D.
Wishart, Thomas M.
Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
title Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
title_full Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
title_fullStr Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
title_full_unstemmed Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
title_short Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
title_sort proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622084/
https://www.ncbi.nlm.nih.gov/pubmed/28963550
http://dx.doi.org/10.1038/s41598-017-12603-0
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