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Munc13-1 restoration mitigates presynaptic pathology in spinal muscular atrophy

Author

Listed:
  • Mehri Moradi

    (University Hospital Wuerzburg)

  • Julia Weingart

    (Julius-Maximilians-University Wuerzburg)

  • Chunchu Deng

    (University Hospital Wuerzburg
    Jiefang Avenue)

  • Mahoor Nasouti

    (University Hospital Wuerzburg
    Charité-Universitätsmedizin Berlin)

  • Michael Briese

    (University Hospital Wuerzburg)

  • Sibylle Jablonka

    (University Hospital Wuerzburg)

  • Markus Sauer

    (Julius-Maximilians-University Wuerzburg)

  • Michael Sendtner

    (University Hospital Wuerzburg)

Abstract

Degeneration of neuromuscular synapses is a key pathological feature of spinal muscular atrophy (SMA), yet cellular mechanisms underlying synapse dysfunction remain elusive. Here, we show that pharmacological stimulation with Roscovitine triggers the assembly of Munc13-1 release sites that relies on its local translation. Our findings show that presynaptic mRNA levels and local synthesis of Munc13-1 are diminished in motoneurons from SMA mice and hiPSC-derived motoneurons from SMA patients. Replacement of the Munc13-1 3’UTR with that of Synaptophysin1 rescues Munc13-1 mRNA transport in SMA motoneurons and restores the nanoscale architecture of presynaptic Munc13-1 release sites. Restoration of Munc13-1 levels leads to functional synaptic recovery in cultured SMA motoneurons. Furthermore, SMA mice cross-bred with a conditional knock-in mouse expressing modified Munc13-1 with a heterologous 3’UTR display attenuated synapse and neurodegeneration and improved motor function. Identifying Munc13-1 as an SMA modifier underscores the potential of targeting synapses to mitigate neuromuscular dysfunction in SMA.

Suggested Citation

  • Mehri Moradi & Julia Weingart & Chunchu Deng & Mahoor Nasouti & Michael Briese & Sibylle Jablonka & Markus Sauer & Michael Sendtner, 2025. "Munc13-1 restoration mitigates presynaptic pathology in spinal muscular atrophy," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64164-w
    DOI: 10.1038/s41467-025-64164-w
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