Munc13-1 restoration mitigates presynaptic pathology in spinal muscular atrophy

Mehri Moradi (), Julia Weingart, Chunchu Deng, Mahoor Nasouti, Michael Briese, Sibylle Jablonka, Markus Sauer and Michael Sendtner ()
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Mehri Moradi: University Hospital Wuerzburg
Julia Weingart: Julius-Maximilians-University Wuerzburg
Chunchu Deng: University Hospital Wuerzburg
Mahoor Nasouti: University Hospital Wuerzburg
Michael Briese: University Hospital Wuerzburg
Sibylle Jablonka: University Hospital Wuerzburg
Markus Sauer: Julius-Maximilians-University Wuerzburg
Michael Sendtner: University Hospital Wuerzburg

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64164-w

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