The discovery, published in the journal Ageing Cell, could hold the key to developing therapies for devastating age-related diseases such as motor neuron disease (MND), Alzheimer’s disease, and Parkinson’s disease.
Hope: Dr Sina Shadfar, pictured, and colleagues discovered a protein which they have shown for the first time acts like a 'glue', helping to repair broken DNA, which is widely accepted as one of the main contributors to ageing and the progression of age-related diseases.
The research, conducted by neurobiologist Dr Sina Shadfar and colleagues in the Motor Neuron Disease Research Centre, reveals a protein called protein disulphide isomerase (PDI) helps repair serious deoxyribonucleic acid (DNA) damage. This breakthrough opens new possibilities for therapies aimed at boosting the body’s ability to fix its own DNA — a process that becomes less efficient as we age.
“Just like a cut on your skin needs to heal, the DNA in our cells needs constant repair,” says Dr Shadfar.
“Every day, individual cells suffer thousands of tiny hits to their DNA — from both within our own bodies and from environmental stressors like pollution or UV light. Normally, the body responds quickly. But as we age, these repair mechanisms weaken, allowing damage to build up.”
This accumulation of DNA damage is now widely accepted as one of the major contributors to ageing and the progression of age-related diseases, particularly those that affect the brain.
“Brain cells are especially vulnerable,” Dr Shadfar explains. “Unlike skin or blood cells, they don’t divide or renew — so any damage that builds up in them stays. And if the damage isn’t repaired, it can eventually lead to the death of these critical cells.”
The unexpected role of a ‘shape-shifting’ protein
PDI is typically found in the cytoplasm — the outer region of the cell — where it helps fold proteins into their proper shapes. But Dr Shadfar’s team made a surprising discovery: PDI can also move into the nucleus — the control centre of the cell — and play a vital role in repairing ddouble-strand breaks, one of the most dangerous types of DNA damage.
We’re not just looking to slow these diseases down. With continued research and innovation, we truly believe we can defeat them.
“Until now, we didn’t know why PDI sometimes appeared in the nucleus,” says Dr Shadfar. “For the first time, we’ve shown it acts like a glue or catalyst, helping to repair broken DNA in both dividing and non-dividing cells.”
The team demonstrated this by stimulating DNA damage in both human cancer cells and mouse brain cells in the lab. When PDI was removed, the cells struggled to repair themselves. When PDI was added back in, DNA repair improved. They also tested this in live zebrafish and found that boosting PDI production helped protect the animals from age-related DNA damage.
A protein with two faces
PDI has previously been studied in cancer research — and not always in a positive light. Tumours often show high levels of PDI, where cancer cells appear to exploit its DNA repair abilities to help them survive and resist treatment. “PDI is like a double agent,” Dr Shadfar explains. “In healthy cells, it repairs DNA and helps prevent disease. But in cancer, it gets hijacked — it ends up protecting the tumour instead of the body. That’s why understanding it fully is so important.”
Building on knowledge: Dr Shadfar and the Research Centre team are using gene therapies, including the same technology used in COVID-19 vaccines, to target ageing mechanisms that overlap with those found in MND.
This dual role of PDI may also offer new ways to make chemotherapy more effective by turning off the protein’s protective function in cancer cells — while boosting it in brain cells where DNA repair is most needed. However, because of this duality, any therapy that modulates PDI will need to be precisely targeted to avoid unintended effects — helping the right cells while not empowering the wrong ones.
Dr Shadfar is using novel, highly specific gene delivery approaches to ensure that the therapy reaches brain cells where it’s needed most, while minimising off-target effects in other parts of the body.
Hope for gene therapy targeting brain ageing
While enhancing DNA repair has long been considered a promising path for treating ageing-related conditions, no gene therapies have yet reached the clinic. Dr Shadfar and his team are now working on changing that.
We’re utilizing gene therapy approaches — including one using mRNA, the same technology used in COVID-19 vaccines — to target ageing mechanisms that overlap with those found in MND. This project was recently awarded $300,000 by FightMND, Australia’s leading not-for-profit organisation for MND research, and represents Australia's first mRNA-based therapy aimed at tackling MND from an ageing perspective.
“This work has the potential to transform how we approach neurodegenerative diseases,” says Dr Shadfar.
“We want to intervene earlier — before too much damage is done. Our ultimate goal is to prevent or halt the progression of these devastating conditions."
A growing need for new solutions
As Australia’s population continues to age, the personal and economic toll of age-related diseases is expected to rise sharply.
“By 2050, one in four Australians will be over 65,” Dr Shadfar says. “MND deaths have increased by 250 per cent over the past 30 years. Cases of dementia, including Alzheimer’s disease, are projected to more than double by 2041. Parkinson’s disease, now the fastest-growing neurological disorder, affects over 150,000 Australians — and is increasing at 4 per cent each year.”
Dr Sina Shadfar is a neurobiologist in the Macquarie University Motor Neuron Disease Research Centre.
With over 12 years of experience in neurodegeneration research, Dr Shadfar has received numerous national and international awards for scientific excellence. His work has led to key collaborations with leading research institutions around the world, and his leadership on gene and mRNA therapy projects is helping pave the way for next-generation treatments for age-related disorders.
