Warwick Medical School researchers will lead an ERC Synergy project to uncover the rules of the road for the longest cells in the human body.
Inside our nerve cells runs one of the most demanding road networks in biology. Packages must travel along microscopic motorways, through spaces barely wider (and sometimes smaller) than the cargo itself, over distances of up to a metre in humans when neurons run from the spinal cord to the toes.
A new international project, led by researchers at the University of Warwick, TUD Dresden University of Technology and the University of Göttingen, aims to uncover the rules that keep this traffic flowing. The European Research Council (ERC) is funding the project with a Synergy Grant of €10.3 million over six years, Warwick will receive €4.3 million.
When the traffic stops
The motorways in neurons are built from protein filaments called microtubules. Tiny molecular motors act as the vehicles, hauling cargo along them. Some loads carry energy supplies, others carry signalling molecules, and they travel at different speeds, some heading out from the cell body and others heading back. The roads are narrow and extremely busy, with cargoes constantly meeting head-on or trying to overtake. How they get past each other without bringing the whole network to a standstill is not understood.
Professor Anne Straube, Centre for Mechanochemical Cell Biology, Warwick Medical School, said: "Imagine a transcontinental motorway with many lanes but no central barrier, on which cars and lorries are going in both directions, some are crawling while others are racing. Many lorries have abnormally wide loads that straddle several lanes or are as wide as the entire motorway itself. That is what the inside of a nerve cell looks like. Somehow cargo gets past without constant jams or pileups, but how our cells manage that is still a mystery. We are now setting out to discover the rules of the neuronal road."
Transport inside cells is a delicate balance and if this is disturbed, the longest nerve cells are often the first to suffer. Defects in intracellular transport have been linked to inherited neurological conditions including Charcot-Marie-Tooth disease, hereditary spastic paraplegia and spinal muscular atrophy, which damage the nerves controlling movement and sensation. Wider transport defects are also implicated in motor neurone disease (ALS), Alzheimer's and Parkinson's disease.
Three ways to study one transport network
The TransportRules project brings together three groups: Professor Straube at the Centre for Mechanochemical Cell Biology in Warwick, Professor Stefan Diez at the B CUBE - Center for Molecular Bioengineering in Dresden, and Professor Stefan Klumpp at the Institute for the Dynamics of Complex Systems in Göttingen.
At Warwick, Professor Straube's team will carry out a systematic traffic survey in living human neurons grown from stem cells. Like a traffic census, it will cover eight major types of cargo, measuring how fast each travels, how often it stops or turns back, and what happens when two meet. The team will also look for signs of organised traffic, such as separate lanes for fast and slow loads, or convoys of cargo travelling together.
In Dresden, researchers will build the road network from scratch in the laboratory, using engineered tracks and adjustable artificial cargoes to recreate long, busy, multilane roads and collisions. In Göttingen, computer simulations and mathematical models will allow understanding how all the parts work together and reveal underlying rules.
"We will design networks of extremely thin tracks, similar to those used for transport in nerve cells, and build artificial, adjustable packages to test how different types of cargo move along these tracks," explains Professor Stefan Diez, TUD Dresden University of Technology. "This will also allow us to study traffic jams and collisions."
"Understanding how traffic inside the nerve cells works requires us to combine our different perspectives. Only through close collaboration can we answer questions that none of the three groups could tackle alone," adds Professor Stefan Klumpp, University of Göttingen.
