Mechanisms underlying axonal transport defects in MND

Description:

What this research means to you: Recent evidence suggests that in the earliest stages of MND, the ends of motor neurons “die back” from the muscles they control. This project will investigate the idea that “dying back” happens because of a failure of the transport systems that move essential supplies to the far end of the neuron. The researchers will use a mouse model of MND to better understand how the transport system goes wrong, with the ultimate aim of working out how the problem can be corrected.

The researchers explain in more detail: Inside all cells, tiny molecular “motors” are responsible for transporting cargoes such as nutrients and cellular components. In motor neurons this transport must occur in two directions, and over great distances, since the neuron can be over 1 metre long. We have already shown that failure of transport in motor neurons occurs early in the development of the disease.

Mitochondria are an important cargo – these cellular components generate energy for the motor neuron. We recently discovered that the transport of mitochondria is only disturbed in one direction: out towards the end of the neuron where it meets the muscle. This leads to a lack of mitochondria in the motor neuron nerve fibre, particularly at the far end, resulting in an energy deficit for these parts of the cell. This will cause the motor neurons to stop working properly and ultimately will contribute to their death, with the degeneration starting at the far end; this is consistent with the “dying back” pattern seen in MND.

We think that restoring the correct transport of mitochondria in motor neurons of MND patients would be beneficial, and the aim of this project is to increase our understanding of the biology of mitochondrial transport in MND. We will determine which parts of the molecular motors are defective and why. This will allow us to design therapeutic approaches that correct the mitochondrial transport defect in MND. We hope that in the future, drugs that we identify will be used for the treatment of MND.