Published on: Jun 17, 2025
Macquarie University scientists have uncovered a major clue in the fight against age-related diseases — a naturally occurring human protein that acts like molecular 'glue' to repair broken DNA, a process essential for healthy aging.
Published in Ageing Cell, this landmark study reveals how a protein called protein disulphide isomerase (PDI) helps fix severe DNA damage — a leading contributor to neurodegenerative diseases such as motor neuron disease (MND), Alzheimer’s, and Parkinson’s disease.
Just like a cut on your skin needs to heal, the DNA in our cells needs constant repair,” explains Dr Sina Shadfar, lead author and neurobiologist at the Motor Neuron Disease Research Centre.
Each day, our cells endure thousands of DNA “hits” from internal stress and external factors like pollution and UV radiation. While youthful cells repair this damage efficiently, aging diminishes these repair systems — allowing harmful mutations to accumulate, particularly in brain cells that don’t regenerate.
A Surprising Role for a ‘Shape-Shifting’ Protein
PDI has long been known for helping proteins fold properly in the cytoplasm. But Dr Shadfar's team made a surprising discovery: PDI also travels into the cell nucleus, where it actively repairs double-strand DNA breaks — the most dangerous form of genetic damage.
“Until now, we didn’t know why PDI sometimes appeared in the nucleus, says Dr Shadfar. For the first time, we’ve shown it behaves like a catalyst — or ‘glue’ — restoring DNA integrity in both dividing and non-dividing cells.
Their findings were validated across multiple models — including human cancer cells, mouse brain cells, and live zebrafish. When PDI was removed, DNA repair faltered. When it was reintroduced, repair improved significantly.
A Double Agent in Disease and Healing
PDI has been studied in cancer, where tumors exploit its DNA-repairing ability to resist treatment. This dual identity — healer in healthy cells, helper in tumors — makes it both promising and challenging as a therapeutic target.
“PDI is like a double agent, says Dr Shadfar. “To harness its benefits, we need precise targeting — boosting it in brain cells while avoiding unintended effects elsewhere.
mRNA Gene Therapy to Combat Brain Aging
Dr Shadfar’s team is now developing gene therapies using mRNA technology, the same platform used in COVID-19 vaccines, to deliver PDI-enhancing treatments directly to brain cells. Their project — recently awarded $300,000 by FightMND — is Australia’s first mRNA-based therapy targeting MND through the lens of aging.
“We’re not just trying to slow these diseases down,” says Dr Shadfar. “We want to stop them before irreversible damage occurs.”
A Race Against Time
As Australia’s population ages, the urgency for innovative treatments grows. By 2050, one in four Australians will be over 65. MND deaths have surged 250% in 30 years, and dementia cases are expected to more than double by 2041. Parkinson’s disease — already affecting 150,000 Australians — is now the country’s fastest-growing neurological condition.
A Vision for the Future
With over 12 years of experience in neurodegeneration research, Dr Sina Shadfar has received numerous national and international awards. His work is forging global collaborations and advancing next-generation therapies that may one day prevent — not just manage — age-related diseases.
This research marks a turning point,” says Dr Shadfar. “By empowering the body to repair its own DNA, we’re unlocking new hope for healthy aging and long-term brain health.
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