VAPB and axonal transport in motor neuron disease

Description:

What this research means to you: Motor neurons can be as long as a metre. This means that essential components and nutrients must be transported over relatively large distances from the neuron’s “headquarters” (cell body) to the far end where the neuron meets the muscle. This project aims to investigate how mistakes in a gene called VAPB, which are associated with a rare, inherited form of MND, disrupt the transport process. A better understanding of these transport problems could indicate potential treatment strategies for all types of MND.

The researchers explain in more detail: Motor neurons have long extensions called axons that reach out from the cell body to connect with other motor neurons or with muscles. Most of the important components of axons are synthesised in the cell body and are then carried into the axon by a process termed “axonal transport”. We now know that this process goes wrong in motor neuron disease (MND) and also that it is one of the earliest (and possibly the earliest) defect. This means that damage to axonal transport is an important part of the disease process and could be a possible target for drugs to treat MND. However, for it to be a viable target, we need to know more about the mechanisms by which it is disrupted.

Mutations (mistakes) in the gene for Cu/Zn superoxide dismutase-1 (SOD1) cause some familial forms of MND and several research groups have shown that the mutants damage mitochondria. (Mitochondria are the motor neurons’ “power stations” and supply the energy for the neuron.) However, whether this damage to mitochondria is linked to problems with axonal transport, or whether it involves a different mechanism has not been clear. Recently, we have shown that mutant SOD1 does damage axonal transport of mitochondria and so it seems that the two insults are related. We now want to see whether other mutant genes that cause MND also damage both mitochondria and axonal transport. This project is to determine whether a mutant form of VAPB, which causes familial MND, damages mitochondria and axonal transport. If this proves to be the case, it will strongly highlight damage to mitochondria and axonal transport of mitochondria as a major toxic “hit” for motor neurons in MND. As such, these studies could reveal new therapeutic targets for the treatment of the disease.