New Australian research brings us closer to viable treatments for motor neuron disease 

Two new Australian studies have identified previously unknown biochemical changes in a protein affected by motor neuron disease (MND), research which could eventually help to develop viable treatments.

In 2015, motor neuron disease was estimated to affect more than 2,000 people in Australia. MND is an umbrella term for a group of neurodegenerative diseases which affect nerves in the brain and spinal cord, known as motor neurons, which relay information to muscles to tell them what to do.

The disease causes progressive loss of voluntary muscle control with each person with MND experiencing a range of symptoms which progress at varying rates. 

The most common form of motor neuron disease is amyotrophic lateral sclerosis (ALS) and one hallmark of is the pathological aggregation of a protein called TAR DNA binding protein 43 (TDP-43).

However, until now the mechanisms behind this disfunction were poorly understood.

The two new studies have been published in the journals Cellular and Molecular Life Sciences and Molecular Psychiatry.

“TDP-43 is a protein found in every cell of the body but is particularly important for the health of motor neurons, the brain cells that control voluntary muscle movement,” syas Dr Adam Walker, from the Queensland Brain Institute at UQ, a senior author on both papers.

“We ran two research projects, looking at how TDP-43 proteins become dysfunctional in motor neurons. We found diseased versions of TDP-43 can damage healthy versions of the protein, which may create a cycle of protein dysfunction and degeneration over time. 

To do this the team used CRISPR/Cas9 to introduce fluorescent tags to the TDP-43 protein.

“It allowed us to see TDP-43 in live cells for the first time,” says Walker. 

This enabled them to visualise how disease-associated stressors and dysfunctional TDP-43 could alter the way that TDP-43 behaves within the cell.

Co-author Sean Keating says they also found that neural pathways change as motor neuron disease progresses, indicating the potential need for different treatments at different phases of the disease.

“We also discovered that biochemical pathways which control neuron death are triggered early, even before MND symptoms begin,” says Keating, who is a PhD student from UQ.

“To change the course of the disease we need pharmaceutical drugs that can prevent neuron death and this TDP-43 protein dysfunction.”

The next steps for the team will involve testing those potential treatments.

“We are now treating genetically modified mice with MND with different pharmaceutical drugs that specifically target the underlying causes of the disease, and correct the disease mechanism,” Keating says.

“Our aim is to stop the TDP-43 degenerative cycle and halt the progression of the disease.

“This research improves our understanding of MND, and we hope it will play an important role in the fight against the disease.”