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New paper in Neuron highlights importance of slow axonal transport in motor neuron function; implications for neuromuscular diseases

20 June 2016

“This excellent work from Alison Twelvetrees at the Institute of Neurology demonstrates the importance of slow axonal
transport which is highly relevant to our understanding of motor neuron function and neuromuscular diseases” Gipi Schiavo Wellcome Senior Investigator and Professor of Cellular Neurobiology

Twelvetrees AE, Pernigo S, Sanger A, Guedes-Dias P, Schiavo G, Steiner RA, Dodding MP, Holzbaur EL. The Dynamic Localization of Cytoplasmic Dynein in Neurons Is Driven by Kinesin-1.  Neuron. 2016 Jun 1;90(5):1000-15.

Dr Alison Twelvetrees explains her findings:

“Neurons form very long extensions, called axons, to reach their targets, make synapses and transmit signals. Axons can be very long; some motor neurons, for example, have their cell bodies in the spinal cord, but extend axons down to the muscles of the hands and feet to control movement.

This creates a problem for neurons as the majority of the protein they need to function is made in the cell body, which can be up to 1 metre away from where it’s needed at the synapse. In addition, neuronal survival depends on essential retrograde trafficking events, such as neurotrophic signalling, from the synapse back to the cell body.

To carry out essential long range transport neurons use a system of cellular motorways, called microtubules, and nano-motors, to step along the microtubule tracks. Within the axon, there are both forward motors (called kinesins), and reverse motors (called cytoplasmic dyneins), responsible for delivering newly made protein and retrograde signalling respectively.

The retrograde motor cytoplasmic dynein is itself made in the cell body, but is required out at the ends of axons to power transport back towards the cell body. The accumulation of dynein in the ends of axons is essential to normal neuronal function, but how this is achieved is unknown. It is important to understand this process as dynein is an essential neuronal motor, and mutations in dynein lead to neurodevelopmental and neurodegenerative diseases.

The transport of newly made protein down the axon has been divided into two broad catergories based on speed; fast and slow. For a 1 metre axon, fast transport takes around 1 week to deliver cargo whereas slow transport can take up to a year. Kinesins are known as the motors that power fast transport, but very little is known about the mechanisms that mediate slow transport.

Previous studies have indicated that cytoplasmic dynein is delivered to the ends of axons at the speed of slow transport. In this study, we have established that the forward slow axonal transport of dynein is also dependent on direct interactions with kinesin.

We propose a model whereby the slow transport of dynein is driven by short, transient interactions with kinesin due to a limited ability to recruit and hold kinesin in an active state, within an environment with a limited supply of available kinesin motors.

Slow moving cargoes such as dynein can directly associate with kinesin for short bursts of motility. By combining a limited ability to hold kinesin in an active state with a relatively low supply of active kinesin motors, slow transport cargoes would move much more slowly relative to kinesin due to the constant binding and release of cargo producing short bursts of motility.

The study of slow axonal transport has been very challenging due the to slow time scale of the overall transport rates, and the indistinct nature of the transport unit for cytosolic cargoes. However, at least three times the amount of protein is delivered to synapses by slow compared to fast transport, making this the major protein delivery system.

We have established new imaging and analysis tools for the study of slow transport in real time and in the process, the first set of molecular level details for a cytosolic slow transport complex.

Going forward, these tools can now be used to probe the underlying principles of slow axonal transport; in particular, providing insights into the difference between kinesin recruitment for slow compared fast axonal transport.”

Further information