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鈥淭his 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鈥� 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.聽 Neuron. 2016 Jun 1;90(5):1000-15.

Dr Alison Twelvetrees explains her findings:

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

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

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

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

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

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

We聽propose a model whereby the slow transport of dynein is driven by short, transient interactions with kinesin聽due to聽a limited ability to recruit and hold聽kinesin in an active state, within an environment with a limited聽supply of available聽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聽transport聽rates, and the indistinct nature of the transport unit for cytosolic cargoes. However,聽at least three聽times the amount of protein is delivered to synapses by slow compared to聽fast transport, making this the聽major protein delivery system.

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

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

Further information

• Twelvetrees AE, Pernigo S, Sanger A, Guedes-Dias P, Schiavo G, Steiner RA, Dodding MP, Holzbaur EL. .Neuron. 2016 Jun 1;90(5):1000-15. doi: 10.1016/j.neuron.2016.04.046. Epub 2016 May 19.PMID: 27210554
• YouTube video聽explaining聽the paper :
• The paper is previewed in the Neuron issue: