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Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network thro...

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Autores principales: Beltran, S., Nassif, M., Vicencio, E., Arcos, J., Labrador, L., Cortes, B. I., Cortez, C., Bergmann, C. A., Espinoza, S., Hernandez, M. F., Matamala, J. M., Bargsted, L., Matus, S., Rojas-Rivera, D., Bertrand, M. J. M., Medinas, D. B., Hetz, C., Manque, P. A., Woehlbier, U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437924/
https://www.ncbi.nlm.nih.gov/pubmed/30917850
http://dx.doi.org/10.1186/s13024-019-0313-9
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author Beltran, S.
Nassif, M.
Vicencio, E.
Arcos, J.
Labrador, L.
Cortes, B. I.
Cortez, C.
Bergmann, C. A.
Espinoza, S.
Hernandez, M. F.
Matamala, J. M.
Bargsted, L.
Matus, S.
Rojas-Rivera, D.
Bertrand, M. J. M.
Medinas, D. B.
Hetz, C.
Manque, P. A.
Woehlbier, U.
author_facet Beltran, S.
Nassif, M.
Vicencio, E.
Arcos, J.
Labrador, L.
Cortes, B. I.
Cortez, C.
Bergmann, C. A.
Espinoza, S.
Hernandez, M. F.
Matamala, J. M.
Bargsted, L.
Matus, S.
Rojas-Rivera, D.
Bertrand, M. J. M.
Medinas, D. B.
Hetz, C.
Manque, P. A.
Woehlbier, U.
author_sort Beltran, S.
collection PubMed
description BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. METHODS: Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1(G93A) and TDP43(A315T)) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. RESULTS: Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. CONCLUSIONS: This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-019-0313-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-64379242019-04-08 Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis Beltran, S. Nassif, M. Vicencio, E. Arcos, J. Labrador, L. Cortes, B. I. Cortez, C. Bergmann, C. A. Espinoza, S. Hernandez, M. F. Matamala, J. M. Bargsted, L. Matus, S. Rojas-Rivera, D. Bertrand, M. J. M. Medinas, D. B. Hetz, C. Manque, P. A. Woehlbier, U. Mol Neurodegener Research Article BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. METHODS: Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1(G93A) and TDP43(A315T)) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. RESULTS: Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. CONCLUSIONS: This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-019-0313-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-27 /pmc/articles/PMC6437924/ /pubmed/30917850 http://dx.doi.org/10.1186/s13024-019-0313-9 Text en © The Author(s). 2019 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
Beltran, S.
Nassif, M.
Vicencio, E.
Arcos, J.
Labrador, L.
Cortes, B. I.
Cortez, C.
Bergmann, C. A.
Espinoza, S.
Hernandez, M. F.
Matamala, J. M.
Bargsted, L.
Matus, S.
Rojas-Rivera, D.
Bertrand, M. J. M.
Medinas, D. B.
Hetz, C.
Manque, P. A.
Woehlbier, U.
Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
title Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
title_full Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
title_fullStr Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
title_full_unstemmed Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
title_short Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
title_sort network approach identifies pacer as an autophagy protein involved in als pathogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437924/
https://www.ncbi.nlm.nih.gov/pubmed/30917850
http://dx.doi.org/10.1186/s13024-019-0313-9
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