Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

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

doi:10.1038/s41467-025-59679-1

Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

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^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	4633
Journal	Nature communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-59679-1
Publication status	Published - 19 May 2025

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Schweingruber, C., Nijssen, J., Mechtersheimer, J., Reber, S., Lebœuf, M., O’Brien, N. L., Mei, I., Hedges, E., Keuper, M., Benitez, J. A., Radoi, V., Jastroch, M., Ruepp, M.-D., & Hedlund, E. (2025). Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS. Nature communications, 16(1), Article 4633. https://doi.org/10.1038/s41467-025-59679-1

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title = "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 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.",

author = "Christoph Schweingruber and Jik Nijssen and Jonas Mechtersheimer and Stefan Reber and M{\'e}lanie Leb{\oe}uf and O{\textquoteright}Brien, {Niamh L.} and Irene Mei and Erin Hedges and Michaela Keuper and Benitez, {Julio Aguila} and Vlad Radoi and Martin Jastroch and Marc-David Ruepp and Eva Hedlund",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

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doi = "10.1038/s41467-025-59679-1",

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Schweingruber, C, Nijssen, J, Mechtersheimer, J , Reber, S, Lebœuf, M, O’Brien, NL, Mei, I, Hedges, E, Keuper, M, Benitez, JA, Radoi, V, Jastroch, M, Ruepp, M-D & Hedlund, E 2025, 'Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS', Nature communications, vol. 16, no. 1, 4633. https://doi.org/10.1038/s41467-025-59679-1

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T1 - Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

AU - Schweingruber, Christoph

AU - Nijssen, Jik

AU - Mechtersheimer, Jonas

AU - Reber, Stefan

AU - Lebœuf, Mélanie

AU - O’Brien, Niamh L.

AU - Mei, Irene

AU - Hedges, Erin

AU - Keuper, Michaela

AU - Benitez, Julio Aguila

AU - Radoi, Vlad

AU - Jastroch, Martin

AU - Ruepp, Marc-David

AU - Hedlund, Eva

PY - 2025/5/19

Y1 - 2025/5/19

N2 - 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.

AB - 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.

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JO - Nature communications

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ER -

Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

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