Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
Abstract Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37630-6 |
| _version_ | 1827961223052787712 |
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| author | Oliver J. Ziff Jacob Neeves Jamie Mitchell Giulia Tyzack Carlos Martinez-Ruiz Raphaelle Luisier Anob M. Chakrabarti Nicholas McGranahan Kevin Litchfield Simon J. Boulton Ammar Al-Chalabi Gavin Kelly Jack Humphrey Rickie Patani |
| author_facet | Oliver J. Ziff Jacob Neeves Jamie Mitchell Giulia Tyzack Carlos Martinez-Ruiz Raphaelle Luisier Anob M. Chakrabarti Nicholas McGranahan Kevin Litchfield Simon J. Boulton Ammar Al-Chalabi Gavin Kelly Jack Humphrey Rickie Patani |
| author_sort | Oliver J. Ziff |
| collection | DOAJ |
| description | Abstract Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response. |
| first_indexed | 2024-04-09T16:23:16Z |
| format | Article |
| id | doaj.art-dd8f26a91a1646ca8fb84eb2c02762b3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T16:23:16Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-dd8f26a91a1646ca8fb84eb2c02762b32023-04-23T11:22:17ZengNature PortfolioNature Communications2041-17232023-04-0114111610.1038/s41467-023-37630-6Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathologyOliver J. Ziff0Jacob Neeves1Jamie Mitchell2Giulia Tyzack3Carlos Martinez-Ruiz4Raphaelle Luisier5Anob M. Chakrabarti6Nicholas McGranahan7Kevin Litchfield8Simon J. Boulton9Ammar Al-Chalabi10Gavin Kelly11Jack Humphrey12Rickie Patani13The Francis Crick InstituteThe Francis Crick InstituteThe Francis Crick InstituteThe Francis Crick InstituteCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer InstituteGenomics and Health Informatics Group, Idiap Research InstituteThe Francis Crick InstituteCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer InstituteCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer InstituteThe Francis Crick InstituteMaurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonThe Francis Crick InstituteNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount SinaiThe Francis Crick InstituteAbstract Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.https://doi.org/10.1038/s41467-023-37630-6 |
| spellingShingle | Oliver J. Ziff Jacob Neeves Jamie Mitchell Giulia Tyzack Carlos Martinez-Ruiz Raphaelle Luisier Anob M. Chakrabarti Nicholas McGranahan Kevin Litchfield Simon J. Boulton Ammar Al-Chalabi Gavin Kelly Jack Humphrey Rickie Patani Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology Nature Communications |
| title | Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology |
| title_full | Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology |
| title_fullStr | Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology |
| title_full_unstemmed | Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology |
| title_short | Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology |
| title_sort | integrated transcriptome landscape of als identifies genome instability linked to tdp 43 pathology |
| url | https://doi.org/10.1038/s41467-023-37630-6 |
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