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
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.
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.
Does this mean they believe this Lingo-1 can actually promote the regrowth of dead axons in the CNS? That's reAlly cool if it can.
ReplyDeleteI wish......
ReplyDeleteThey are targetting remyelination any
regrowth of damaged axons (dead is dead) could be a plus