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 () and Eva Hedlund ()
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Christoph Schweingruber: Stockholm University
Jik Nijssen: Karolinska Institutet, Biomedicum
Jonas Mechtersheimer: Maurice Wohl Clinical Neuroscience Institute
Stefan Reber: Maurice Wohl Clinical Neuroscience Institute
Mélanie Lebœuf: Stockholm University
Niamh L. O’Brien: Maurice Wohl Clinical Neuroscience Institute
Irene Mei: Stockholm University
Erin Hedges: Maurice Wohl Clinical Neuroscience Institute
Michaela Keuper: Stockholm University
Julio Aguila Benitez: Karolinska Institutet, Biomedicum
Vlad Radoi: Stockholm University
Martin Jastroch: Stockholm University
Marc-David Ruepp: Maurice Wohl Clinical Neuroscience Institute
Eva Hedlund: Stockholm University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59679-1

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