Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS

Santiago Mora, Anna Stuckert, Rasmus Huth Friis, Kimberly Pietersz, Gith Noes-Holt, Roser Montañana-Rosell, Haoyu Wang, Andreas Toft Sørensen, Raghavendra Selvan, Joost Verhaagen and Ilary Allodi ()
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Santiago Mora: University of Copenhagen
Anna Stuckert: University of Copenhagen
Rasmus Huth Friis: University of Copenhagen
Kimberly Pietersz: The Netherlands Institute for Neuroscience
Gith Noes-Holt: University of Copenhagen
Roser Montañana-Rosell: University of Copenhagen
Haoyu Wang: University of St Andrews
Andreas Toft Sørensen: University of Copenhagen
Raghavendra Selvan: University of Copenhagen
Joost Verhaagen: The Netherlands Institute for Neuroscience
Ilary Allodi: University of Copenhagen

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.

Date: 2024
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DOI: 10.1038/s41467-024-48925-7

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