- Researchers at The Florey have for the first time provided direct evidence to support a long-held hypothesis about where motor neurone disease (MND) starts in the body.
- For 30+ years research has supported the ‘dying forward’ hypothesis that MND starts and is driven by overactive motor neurons in the brain, rather than neurons in the spine.
- Cutting-edge technology was used to induce cortical overactivity in mice, leading to hallmark symptoms and pathological features of MND/ALS.
MND driven by overactive motor neurons in the brain
Does MND start in the brain or the spinal cord?
It is a burning question researchers studying the progressive and fatal neurological condition have been unable to answer with certainty because of a lack of direct evidence.
When we undertake a given movement, electrical activity in a population of cells in the brain, known as upper motor neurons, send impulses to the spinal cord where they are relayed to relevant muscles by lower motor neurons.
As both upper and lower neurons die in MND there has been debate as to whether the disease starts in the brain or the spinal cord.
One of the early and common signs of MND, also known as Amyotrophic Lateral Sclerosis (ALS), is the increased firing of motor neurons in the brains of patients diagnosed with the devastating disease.
Leading neurologists have for more than 30 years proposed what is known as the ‘dying forward’ hypothesis – a belief MND starts in the brain rather than the neurons in the spinal cord.
A research team, led by Dr Mouna Haidar from The Florey’s Motor Neurone Disease Group, has for the first time validated this hypothesis, providing direct evidence consistent with MND being a brain disorder driven by neuronal overactivity.
The researchers used innovative technology called chemogenetics to act like a remote control of brain activity. They expressed designer receptors in brain motor neurons of healthy adult mice to chronically fire up their activity.
“This cutting-edge technique allowed us to reach a chronic level of cortical overactivity in the mice, similar to what is seen in the brains of MND patients,” Dr Haidar said.
“Remarkably this was enough to induce MND-like changes in the mice on both a behavioural and cellular level, including muscle weakness, degeneration of spinal neurons and the build-up of the MND signature protein TDP-43.”
Professor Bradley Turner, Head of The Florey’s Motor Neurone Disease Group, said the research provided hope for the more than 2500 Australians diagnosed with MND.
“This is important foundational research that demonstrates the brain is an early player in MND and will hopefully lead to future development of targeted therapies,” Professor Turner said. “Currently the only approved drug we have to treat MND has limited effectiveness overall.”
The research, published in Progress in Neurobiology, was made possible by a FightMND Impact grant.
