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The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis
Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesize...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143529/ https://www.ncbi.nlm.nih.gov/pubmed/35628504 http://dx.doi.org/10.3390/ijms23105694 |
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author | Teyssou, Elisa Chartier, Laura Roussel, Delphine Perera, Nirma D. Nemazanyy, Ivan Langui, Dominique Albert, Mélanie Larmonier, Thierry Saker, Safaa Salachas, François Pradat, Pierre-François Meininger, Vincent Ravassard, Philippe Côté, Francine Lobsiger, Christian S. Boillée, Séverine Turner, Bradley J. Seilhean, Danielle Millecamps, Stéphanie |
author_facet | Teyssou, Elisa Chartier, Laura Roussel, Delphine Perera, Nirma D. Nemazanyy, Ivan Langui, Dominique Albert, Mélanie Larmonier, Thierry Saker, Safaa Salachas, François Pradat, Pierre-François Meininger, Vincent Ravassard, Philippe Côté, Francine Lobsiger, Christian S. Boillée, Séverine Turner, Bradley J. Seilhean, Danielle Millecamps, Stéphanie |
author_sort | Teyssou, Elisa |
collection | PubMed |
description | Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS. |
format | Online Article Text |
id | pubmed-9143529 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91435292022-05-29 The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis Teyssou, Elisa Chartier, Laura Roussel, Delphine Perera, Nirma D. Nemazanyy, Ivan Langui, Dominique Albert, Mélanie Larmonier, Thierry Saker, Safaa Salachas, François Pradat, Pierre-François Meininger, Vincent Ravassard, Philippe Côté, Francine Lobsiger, Christian S. Boillée, Séverine Turner, Bradley J. Seilhean, Danielle Millecamps, Stéphanie Int J Mol Sci Article Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS. MDPI 2022-05-19 /pmc/articles/PMC9143529/ /pubmed/35628504 http://dx.doi.org/10.3390/ijms23105694 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Teyssou, Elisa Chartier, Laura Roussel, Delphine Perera, Nirma D. Nemazanyy, Ivan Langui, Dominique Albert, Mélanie Larmonier, Thierry Saker, Safaa Salachas, François Pradat, Pierre-François Meininger, Vincent Ravassard, Philippe Côté, Francine Lobsiger, Christian S. Boillée, Séverine Turner, Bradley J. Seilhean, Danielle Millecamps, Stéphanie The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis |
title | The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis |
title_full | The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis |
title_fullStr | The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis |
title_full_unstemmed | The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis |
title_short | The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis |
title_sort | amyotrophic lateral sclerosis m114t pfn1 mutation deregulates alternative autophagy pathways and mitochondrial homeostasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143529/ https://www.ncbi.nlm.nih.gov/pubmed/35628504 http://dx.doi.org/10.3390/ijms23105694 |
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