I’m going to stick my neck out a bit here, and discuss some chemical biology, even though I wouldn’t claim to be much of a biology expert. Apologies if some of the details are a bit ropy.
This morning, Linda Hsieh-Wilson gave an inspiring talk on her work unravelling the role of the polysaccharide chondroitin sulfate (CS) in modulating neuron growth. Naturally occurring CS is a mixture of compounds, each containing a different pattern of sulfate groups. This makes it difficult to tease out the effects of particular sulfation patterns, but Hsieh-Wilson’s group have made several tetrasaccharides as models of CS, each with one of the different characteristic arrangements of sulfates found in the parent molecule.
They find that only one of these tetrasaccharides (called CS-E) promotes neuron growth in their in vitro studies. Using CS-E as a molecular probe, they’ve now started to unravel the likely biological mechanism of action. It seems that CS-E forms a ternary complex with brain-derived neurotrophic factor and the receptor TrkB. Blocking formation of this complex prevents CS-E-mediated neurite growth.
But CS is a double-edged sword – it can also prevent neuron regeneration after injury. Hsieh-Wilson is now using her compounds to unpick the reasons for this. Her tetrasaccharides weren’t effective substitutes for CS in in vitro models of neuron regeneration, so her team came up with a method to prepare CS-E polymers (containing 25-80 sugar units). Sure enough, these polymers inhibit neuron regeneration, showing that the CS-E sulfation pattern is most likely responsible for the biological effect. Furthermore, an antibody that blocks CS-E activity was able to counteract the inhibition, thus encouraging neuron repair.
Exciting stuff, especially as there is currently no way to stimulate regeneration of damaged neurons. Of course, this is a long way off providing anything that would be therapeutically useful, but just being able to unpick the biological mechanisms that prevent neuron regeneration strikes me as being incredibly useful. And it’s a perfect example of how chemistry can provide tools that answer biological questions.
Andrew Mitchinson (Senior Editor, Nature)