Multiple sclerosis: Does nogo play a role?

Over the past decade, there has been substantial interest in the role of the integral myelin protein, Nogo-A, from fundamental neurobiological to clinical perspectives. It is now a well-known inhibitor of neurite outgrowth through its cognate receptor, Nogo receptor 1 (NgR1). Nogo-A can only signal through NgR1 upon heteromeric collaboration with p75NTR, TROY, and LINGO-1 to induce axonal retraction. Both Nogo-A and NgR1 are expressed in multiple sclerosis (MS) lesions, suggesting that Nogo signaling may play a pivotal role in disease progression. There are several approaches targeting Nogo signaling in animal models of MS, and these therapeutic effects are currently in debate. One of the points of contention arises from the localization of the aforementioned signaling molecules, considering that MS and its animal models of disease are governed by inflammatory infiltration of the central nervous system. Furthermore, an impressive list of ligands for NgR1 continues to be compiled, possibly leading to disparities in the results obtained from the various animal models. In this review, we systematically dissect the complexities of Nogo signaling, which may be relevant in the future directions of neuroprotective therapies for MS.