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Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice
BACKGROUND: TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192075/ https://www.ncbi.nlm.nih.gov/pubmed/30326935 http://dx.doi.org/10.1186/s13024-018-0288-y |
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author | Beel, Sander Herdewyn, Sarah Fazal, Raheem De Decker, Mathias Moisse, Matthieu Robberecht, Wim Van Den Bosch, Ludo Van Damme, Philip |
author_facet | Beel, Sander Herdewyn, Sarah Fazal, Raheem De Decker, Mathias Moisse, Matthieu Robberecht, Wim Van Den Bosch, Ludo Van Damme, Philip |
author_sort | Beel, Sander |
collection | PubMed |
description | BACKGROUND: TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43-induced neurodegeneration is not yet clear. METHODS: We studied the effect of PGRN on the neurodegenerative phenotype in TDP-43(A315T) mice. RESULTS: PGRN reduced the levels of insoluble TDP-43 and histology of the spinal cord revealed a protective effect of PGRN on the loss of large axon fibers in the lateral horn, the most severely affected fiber pool in this mouse model. Overexpression of PGRN significantly slowed down disease progression, extending the median survival by approximately 130 days. A transcriptome analysis did not point towards a single pathway affected by PGRN, but rather towards a pleiotropic effect on different pathways. CONCLUSION: Our findings reveal an important role of PGRN in attenuating mutant TDP-43-induced neurodegeneration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0288-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6192075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-61920752018-10-23 Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice Beel, Sander Herdewyn, Sarah Fazal, Raheem De Decker, Mathias Moisse, Matthieu Robberecht, Wim Van Den Bosch, Ludo Van Damme, Philip Mol Neurodegener Research Article BACKGROUND: TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43-induced neurodegeneration is not yet clear. METHODS: We studied the effect of PGRN on the neurodegenerative phenotype in TDP-43(A315T) mice. RESULTS: PGRN reduced the levels of insoluble TDP-43 and histology of the spinal cord revealed a protective effect of PGRN on the loss of large axon fibers in the lateral horn, the most severely affected fiber pool in this mouse model. Overexpression of PGRN significantly slowed down disease progression, extending the median survival by approximately 130 days. A transcriptome analysis did not point towards a single pathway affected by PGRN, but rather towards a pleiotropic effect on different pathways. CONCLUSION: Our findings reveal an important role of PGRN in attenuating mutant TDP-43-induced neurodegeneration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0288-y) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-16 /pmc/articles/PMC6192075/ /pubmed/30326935 http://dx.doi.org/10.1186/s13024-018-0288-y 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 Beel, Sander Herdewyn, Sarah Fazal, Raheem De Decker, Mathias Moisse, Matthieu Robberecht, Wim Van Den Bosch, Ludo Van Damme, Philip Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice |
title | Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice |
title_full | Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice |
title_fullStr | Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice |
title_full_unstemmed | Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice |
title_short | Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice |
title_sort | progranulin reduces insoluble tdp-43 levels, slows down axonal degeneration and prolongs survival in mutant tdp-43 mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192075/ https://www.ncbi.nlm.nih.gov/pubmed/30326935 http://dx.doi.org/10.1186/s13024-018-0288-y |
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