EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93Amice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 selectively in these cervical spinal cord astrocytes via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism underlying astrocyte pathogenicity in mutant SOD1-associated ALS and a promising therapeutic target.

Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations

“…More specifically, astrocytes harbouring SOD1 mutations decrease MN survival both in vivo and in vitro (Di Giorgio et al, 2007; Nagai et al, 2007; Marchetto et al, 2008; Meyer et al, 2014). This effect is mediated by cell-to-cell signaling between astrocytes and MNs (Nagai et al, 2007; Fritz et al, 2013; Urban et al, 2023). Little information is available on how SOD1 mutations drive intrinsic changes within astrocytes that affect their cross-talk with MNs.…”