Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation (maturation) of oligodendrocyte precursor cells (OPCs. immature oligodendrocytes) into oligodendrocytes. Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain (area found outside the cell) also had an inhibitory effect on OPCs, and decreased myelinated axonal segments in co-cultures with neurons from dorsal root ganglia (DRG). We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. We observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction. Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination.
Lingo 1 is a molecule that can stop immature oligodendrocytes from maturing in to oligodendrocytes that can make myelin. It is a component within the NOGO receptor complex, which can also stop brain and spinal cord nerves from regrowing via block of a molecule called RhoA that allows the skeleton (cell scaffolding) of a cell to remodel so that it can change shape and grow. In this study it looks like Lingo-1 when made by astrocytes can act as a stimulator (key) of the NOGO complex which has Lingo-1 in it where it acts as a receptor (lock), So when the two come together (homophilic interaction) the key and lock come together to signal the immature oligodendrocyte to mature. It was known that LINGO-1 could act as a lock and Biogen have made a blocker to this and have already started trials. However this new study also indicates that Lingo-1 is a key also and so with a Lingo-1 blocker you get the chance for a double whammy to block the signal that stops myelination. This study by Vertex, another company, could indicate that they are in the hunt for a LINGO-1 blocker also or maybe they have dropped interest in this and this is why they are now talking about this discovery.
Jepson S et al. LINGO-1, A TRANSMEMBRANE SIGNALING PROTEIN, INHIBITS OLIGODENDROCYTE DIFFERENTIATION AND MYELINATION THROUGH INTERCELLULAR SELF-INTERACTIONS. J Biol Chem. 2012 Apr 18. [Epub ahead of print]
Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator (inhibitor) of myelination, is a transmembrane (crosses the cell membrane) signalling protein expressed in both neurons and oligodendrocytes. In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Since the only ligand-binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown. Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular (between cells) interactions