Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS
Abstract Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59679-1 |
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| author | Christoph Schweingruber Jik Nijssen Jonas Mechtersheimer Stefan Reber Mélanie Lebœuf Niamh L. O’Brien Irene Mei Erin Hedges Michaela Keuper Julio Aguila Benitez Vlad Radoi Martin Jastroch Marc-David Ruepp Eva Hedlund |
| author_facet | Christoph Schweingruber Jik Nijssen Jonas Mechtersheimer Stefan Reber Mélanie Lebœuf Niamh L. O’Brien Irene Mei Erin Hedges Michaela Keuper Julio Aguila Benitez Vlad Radoi Martin Jastroch Marc-David Ruepp Eva Hedlund |
| author_sort | Christoph Schweingruber |
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| description | Abstract Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS. |
| format | Article |
| id | doaj-art-bd86cec60f18444e9013046c65488efb |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-bd86cec60f18444e9013046c65488efb2025-08-20T02:29:26ZengNature PortfolioNature Communications2041-17232025-05-0116112210.1038/s41467-025-59679-1Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALSChristoph Schweingruber0Jik Nijssen1Jonas Mechtersheimer2Stefan Reber3Mélanie Lebœuf4Niamh L. O’Brien5Irene Mei6Erin Hedges7Michaela Keuper8Julio Aguila Benitez9Vlad Radoi10Martin Jastroch11Marc-David Ruepp12Eva Hedlund13Department of Biochemistry and Biophysics, Stockholm UniversityDepartment of Cell and Molecular Biology, Karolinska Institutet, BiomedicumUK Dementia Research Institute Centre at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience InstituteUK Dementia Research Institute Centre at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience InstituteDepartment of Biochemistry and Biophysics, Stockholm UniversityUK Dementia Research Institute Centre at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience InstituteDepartment of Biochemistry and Biophysics, Stockholm UniversityUK Dementia Research Institute Centre at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience InstituteDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm UniversityDepartment of Neuroscience, Karolinska Institutet, BiomedicumDepartment of Biochemistry and Biophysics, Stockholm UniversityDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm UniversityUK Dementia Research Institute Centre at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience InstituteDepartment of Biochemistry and Biophysics, Stockholm UniversityAbstract Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.https://doi.org/10.1038/s41467-025-59679-1 |
| spellingShingle | Christoph Schweingruber Jik Nijssen Jonas Mechtersheimer Stefan Reber Mélanie Lebœuf Niamh L. O’Brien Irene Mei Erin Hedges Michaela Keuper Julio Aguila Benitez Vlad Radoi Martin Jastroch Marc-David Ruepp Eva Hedlund Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS Nature Communications |
| title | Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS |
| title_full | Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS |
| title_fullStr | Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS |
| title_full_unstemmed | Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS |
| title_short | Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS |
| title_sort | single cell rna sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across fus and tardbp als |
| url | https://doi.org/10.1038/s41467-025-59679-1 |
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