MRC DTG studentship: Regulation of an axonal survival factor

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

In a normally functioning neuron, the cell body has to supply its axon with all the materials it needs to keep it healthy. This complex logistical process breaks down completely after injury and often becomes compromised in neurodegenerative diseases. When this happens, the isolated axon degenerates. Whilst isolated axons clearly will not be able to exist indefinitely without replenishment of many important cargoes delivered from the cell body, those that are short-lived will be depleted first, so loss of short-lived proteins is likely to act as a stimulus for degeneration. Using clues from a mutant mouse whose axons are protected from degeneration, we have identified delivery of Nmnat2, a protein with an important enzyme activity, as a limiting factor for axon survival. Importantly, Nmnat2 is very short-lived and its levels decline rapidly in injured axons before they start to degenerate. Without it, even uninjured axons degenerate by a similar mechanism, consistent with loss of this protein being a natural stimulus for axon degeneration. This is likely to have important therapeutic implications.

The aims of this project are to understand how the Nmnat2 survival molecule is delivered to axons by the sophisticated molecular machinery in axons, that transports molecules over distances up to a metre long. Like any supply chain, this one dimensional delivery of protein is vulnerable to blockage and axonal degeneration, leading to diseases such as motor neuron disease and Alzheimer’s disease. If we can deliver more of this protein into axons and keep it stable for longer we may be able to delay or prevent such diseases.
 
Description We have understood how a protein required for axons to survive is delivered into axons and learned more about its precise site of action there.
Exploitation Route This will help find ways to keep axons alive in neurodegenerative diseases.
Sectors Healthcare