New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study
Mutations in genes encoding nuclear envelope (NE) proteins, despite being rare, represent a major threat to cell homeostasis by compromising nuclear integrity and function as well as nucleocytoplasmic communication. In the last decade, several diseases have been associated to mutations in the <i&...
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MDPI AG
2023-03-01
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| Series: | Biology and Life Sciences Forum |
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| Online Access: | https://www.mdpi.com/2673-9976/21/1/25 |
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| author | Cátia D. Pereira Guadalupe Espadas Filipa Martins Anne T. Bertrand Laurent Servais Eduard Sabidó Odete A. B. da Cruz e Silva Sandra Rebelo |
| author_facet | Cátia D. Pereira Guadalupe Espadas Filipa Martins Anne T. Bertrand Laurent Servais Eduard Sabidó Odete A. B. da Cruz e Silva Sandra Rebelo |
| author_sort | Cátia D. Pereira |
| collection | DOAJ |
| description | Mutations in genes encoding nuclear envelope (NE) proteins, despite being rare, represent a major threat to cell homeostasis by compromising nuclear integrity and function as well as nucleocytoplasmic communication. In the last decade, several diseases have been associated to mutations in the <i>TOR1AIP1</i> gene that codes for lamina-associated polypeptide 1 (LAP1), a NE protein ubiquitously expressed in human tissues. Although this is suggestive of an important physiological role of LAP1, it remains unclear which cellular activities are regulated by this protein. To address this, we investigated the molecular repercussions of its deficiency in patient-derived skin fibroblasts carrying a pathological LAP1 mutation (p.E482A), previously reported in a case of severe dystonia, cerebellar atrophy and cardiomyopathy. Using liquid chromatography with tandem mass spectrometry (LC–MS/MS), a quantitative proteome analysis was performed to identify up-/downregulated proteins in LAP1 E482A fibroblasts relative to age-matched control fibroblasts. A subsequent functional characterization of the LC–MS/MS-identified differentially expressed proteins using bioinformatics tools unraveled various signaling pathways/biological processes potentially deregulated in LAP1 E482A fibroblasts, such as DNA repair, neurodevelopment and myogenesis, among others. This work sheds light on dysfunctional molecular mechanisms in LAP1-deficient cells, which will contribute to a better understanding of LAP1’s physiological relevance for the maintenance of cell homeostasis and, hopefully, allow the identification of potential therapeutic targets for LAP1-associated pathologies. |
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| institution | Directory Open Access Journal |
| issn | 2673-9976 |
| language | English |
| last_indexed | 2024-03-11T02:41:43Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology and Life Sciences Forum |
| spelling | doaj.art-5b4cb43d62b44f87a0df988e825613f62023-11-18T09:34:11ZengMDPI AGBiology and Life Sciences Forum2673-99762023-03-012112510.3390/blsf2023021025New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics StudyCátia D. Pereira0Guadalupe Espadas1Filipa Martins2Anne T. Bertrand3Laurent Servais4Eduard Sabidó5Odete A. B. da Cruz e Silva6Sandra Rebelo7Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, PortugalCentre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, SpainDepartment of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, PortugalInstitut de Myologie, Center of Research in Myology, INSERM UMRS 974, Medicine Faculty—Sorbonne Université, 75013 Paris, FranceMDUK Oxford Neuromuscular Center, Department of Paediatrics, University of Oxford and NIHR Oxford Biomedical Research Center, Oxford OX3 9DU, UKCentre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, SpainDepartment of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, PortugalDepartment of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, PortugalMutations in genes encoding nuclear envelope (NE) proteins, despite being rare, represent a major threat to cell homeostasis by compromising nuclear integrity and function as well as nucleocytoplasmic communication. In the last decade, several diseases have been associated to mutations in the <i>TOR1AIP1</i> gene that codes for lamina-associated polypeptide 1 (LAP1), a NE protein ubiquitously expressed in human tissues. Although this is suggestive of an important physiological role of LAP1, it remains unclear which cellular activities are regulated by this protein. To address this, we investigated the molecular repercussions of its deficiency in patient-derived skin fibroblasts carrying a pathological LAP1 mutation (p.E482A), previously reported in a case of severe dystonia, cerebellar atrophy and cardiomyopathy. Using liquid chromatography with tandem mass spectrometry (LC–MS/MS), a quantitative proteome analysis was performed to identify up-/downregulated proteins in LAP1 E482A fibroblasts relative to age-matched control fibroblasts. A subsequent functional characterization of the LC–MS/MS-identified differentially expressed proteins using bioinformatics tools unraveled various signaling pathways/biological processes potentially deregulated in LAP1 E482A fibroblasts, such as DNA repair, neurodevelopment and myogenesis, among others. This work sheds light on dysfunctional molecular mechanisms in LAP1-deficient cells, which will contribute to a better understanding of LAP1’s physiological relevance for the maintenance of cell homeostasis and, hopefully, allow the identification of potential therapeutic targets for LAP1-associated pathologies.https://www.mdpi.com/2673-9976/21/1/25LAP1DNA repairneurodevelopmentmyogenesis |
| spellingShingle | Cátia D. Pereira Guadalupe Espadas Filipa Martins Anne T. Bertrand Laurent Servais Eduard Sabidó Odete A. B. da Cruz e Silva Sandra Rebelo New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study Biology and Life Sciences Forum LAP1 DNA repair neurodevelopment myogenesis |
| title | New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study |
| title_full | New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study |
| title_fullStr | New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study |
| title_full_unstemmed | New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study |
| title_short | New Insights on Signaling Pathways Deregulated in LAP1-Deficient Cells: A Proteomics Study |
| title_sort | new insights on signaling pathways deregulated in lap1 deficient cells a proteomics study |
| topic | LAP1 DNA repair neurodevelopment myogenesis |
| url | https://www.mdpi.com/2673-9976/21/1/25 |
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