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Connecting the dots: Abnormal protein may link together all forms of motor neurone disease, USyd study finds

The new finding sheds light on motor neurone disease and suggests improved avenues for treatment.

University of Sydney researchers have found an abnormal protein that may be shared between all forms of motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS). Their findings on the protein, superoxide dismutase 1 (SOD1,) were recently published in the scientific journal Brain. These findings open new pathways of treatment for a severe disease that weakens muscles in the hands, feet, or voice and frequently causes death within five years of diagnosis.

Incorrectly functioning SOD1 was one of the first-identified genetic risk factors for some types of MND. In an interview with Honi, Dr Benjamin Trist, one of the lead authors of the paper and a researcher at the University of Sydney’s Brain and Mind Centre, explained the significance of identifying the prevalence of SOD1 in MND cases.

“I think the most important discovery from this study is that this particular protein was previously only thought to impact about 10 per cent of MND patients. Our findings basically just say that the protein is actually abnormal in all forms of the disorder,” said Trist.

Being aware of  this common protein link will allow scientists to investigate expanded treatment options for a greater number of patients with MND. 

Trist explains that “there are treatments that have been designed to target this protein, and previously they’ve only been tested in that kind of 10% of patients. What our findings mean is that you could apply this treatment to all motor neurone disease patients and it may be able to positively impact a broader spectrum of people.”

Normally, SOD1 is an important protein for maintaining the health of all cells in the body, and protects cells from reactive oxygen chemical species. However, for people with MND, the functions of SOD1 are diminished, rendering it unable to provide adequate protection from these damaging chemical species. The protein has also been identified as toxic to motor neurons themselves in patients who suffer from the disease.

In the laboratory, a lead can announce itself in unexpected ways. Dr Trist and group leader Professor Kay Double were studying metal levels in brains affected by Parkinson’s disease, a type of movement disorder different to MND, when the SOD1 protein captured their attention. Scientists have been aware of this abnormal protein in patients since 1993, but did not understand its ubiquity in MND cases until now.

“This meant that while we were just beginning investigations in Parkinson’s disease, we were able to actually use up this big big body of data in motor neurone disease research to help inform us what could be going on in the Parkinson’s patients.”

After tidying up their Parkinson’s research, they turned their attention to SOD1 and MND, specifically.

The MND study used post-mortem human tissue sourced entirely from donors. Frozen tissue was crushed up and proteins in the tissue cells were separated by size and other factors. SOD1 was identified using antibodies and examined using techniques such as mass spectrometry. Chemically treated sample tissue, which preserves the tissue structure, was able to show the researchers the location and presence of the SOD1 protein in their samples. The protein was found to accumulate in specific parts of spinal cord motor neurons, which is a reliable indicator for all forms of MND.

The paper was coordinated by Dr Benjamin Trist and Professor Kay Double at USyd across five years, and involves the efforts of over thirty people from the UK, France, and the United States.

Dr Trist also highlighted that important scientific findings do not come by without challenges nor significant setbacks.

“When you’re trying to convince people to fund your work you have to convince them that what you’re doing is worthwhile and could be worthwhile; not just for knowledge, but for the patients you’re working to advocate for,” said Trist.

“I think a really important thing for people who are thinking about getting into research to remember is that it doesn’t always work. I had three separate experiments that I spent a year or more working on, cumulatively, that didn’t work. You get to a point where you say, ‘I’m calling this now, cutting my losses, and I’m just going to try something else’. At the time you feel like you’ve wasted six months of your life doing something. It’s a difficult pill to swallow, but it’s all part of it.”

The team is hoping to further investigate whether SOD1 could be a protein to target in treating other disorders, such as Parkinson’s disease. They are also trying to improve on current therapies for SOD1-related cell death by developing better ways to stabilise the protein without removing it from the body altogether.

The paper is open access and can be read on Brain’s website.