NgR1 regulates Caspr dynamics driving axonal degeneration during inflammatory demyelination

Axo-glial units are highly organized microstructures propagating saltatory conduction which are disrupted during multiple sclerosis (MS). Nogo receptor 1 (NgR1) has been suggested to govern axonal damage during MS and in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We have previously identified that naïve ngr1 ^−/− mice display elongated internodes, paranodes, and nodes of Ranvier. Moreover, compound action potentials of optic nerves and spinal cords from naïve ngr1 ^−/− mice were delayed and reduced. Here we show that decreased interaction between the cellular prion protein (PrP ^C ) and Caspr, with enhanced Caspr cleavage occur in EAE-induced ngr1 ^−/− mice. Furthermore, EAE-induced ngr1 ^−/− mice showed preservation in conduction velocity and amplitude at peak stage of disease and did not lead to axonopathy with a reduction in full-length Caspr, but instead its sustained expression. In MS cerebellar white matter tissue, Caspr was found to interact with proteins associated with axonal degeneration and gliosis, highlighting its potential involvement in pathological remodeling of the axo-glial unit. Collectively, our data suggest that NgR1 may partially regulate the axo-myelinic structure through PrP ^c -bound, Caspr-mediated adhesion, which is dysregulated during neuroinflammation leading to axonal damage throughout EAE.