Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis (EAE) preserves axonal transport and abrogates inflammatory demyelination.

We previously identified that ngr1 allele deletion limits the severity of experimental autoimmune encephalomyelitis (EAE) by preserving axonal integrity. However, whether this favorable outcome observed in EAE is a consequence of an abrogated neuronal-specific pathophysiological mechanism, is yet to be defined. Here we show that, Cre-loxP-mediated neuron-specific deletion of ngr1 preserved axonal integrity, whereas its re-expression in ngr1(-/-) female mice potentiated EAE-axonopathy. As a corollary, myelin integrity was preserved under Cre deletion in ngr1(flx/flx), retinal ganglion cell axons whereas, significant demyelination occurred in the ngr1(-/-) optic nerves following the re-introduction of NgR1. Moreover, Cre-loxP-mediated axon-specific deletion of ngr1 in ngr1(flx/flx) mice also demonstrated efficient anterograde transport of fluorescently-labeled ChTx beta in the optic nerves of EAE-induced mice. However, the anterograde transport of ChTx beta displayed accumulation in optic nerve degenerative axons of EAE-induced ngr1(-/-) mice, when NgR1 was reintroduced but was shown to be transported efficiently in the contralateral non-recombinant adeno-associated virus serotype 2-transduced optic nerves of these mutant mice. We further identified that the interaction between the axonal motor protein, Kinesin-1 and collapsin response mediator protein 2 (CRMP2) was unchanged upon Cre deletion of ngr1. Whereas, this Kinesin-1/CRMP2 association was reduced when NgR1 was re-expressed in the ngr1(-/-) optic nerves. Our data suggest that NgR1 governs axonal degeneration in the context of inflammatory-mediated demyelination through the phosphorylation of CRMP2 by stalling axonal vesicular transport. Moreover, axon-specific deletion of ngr1 preserves axonal transport mechanisms, blunting the induction of inflammatory demyelination and limiting the severity of EAE.