Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS. / Mora, Santiago; Stuckert, Anna; von Huth Friis, Rasmus; Pietersz, Kimberly; Noes-Holt, Gith; Montañana-Rosell, Roser; Wang, Haoyu; Sørensen, Andreas Toft; Selvan, Raghavendra; Verhaagen, Joost; Allodi, Ilary.
In: Nature Communications, Vol. 15, No. 1, 4867, 2024, p. 1-16.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
AU - Mora, Santiago
AU - Stuckert, Anna
AU - von Huth Friis, Rasmus
AU - Pietersz, Kimberly
AU - Noes-Holt, Gith
AU - Montañana-Rosell, Roser
AU - Wang, Haoyu
AU - Sørensen, Andreas Toft
AU - Selvan, Raghavendra
AU - Verhaagen, Joost
AU - Allodi, Ilary
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-48925-7
DO - 10.1038/s41467-024-48925-7
M3 - Journal article
C2 - 38849367
AN - SCOPUS:85195428638
VL - 15
SP - 1
EP - 16
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4867
ER -
ID: 395152535