Could this DNA-repairing protein prevent age-related diseases?

Protein disulfide isomerase, or PDI, is a naturally occurring protein found in human cells that, researchers have found, acts as a ‘glue’ helping to repair broken DNA — widely accepted as one of the main contributors to aging and the progression of age-related diseases such as Alzheimer’s, motor neuron and Parkinson’s. The protein could have benefits for therapies aimed at boosting the body’s ability to fix its own DNA — a process of repair that becomes less efficient as people age.

“Just like a cut on your skin needs to heal, the DNA in our cells needs constant repair,” neurobiologist Dr Sina Shadfar explained. “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.”

As we age, this DNA damage accumulates and is now widely accepted as a major contributor to age-related diseases. “Brain cells are especially vulnerable,” Shadfar said. “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.”

Typically found in the outer region of the cell, known as the cytoplasm, PDI helps fold proteins into their proper shapes. But the surprising discovery by Shadfar and his team of researchers at Macquarie University’s Motor Neuron Disease Research Centre — published in open access journal Aging Cell (doi.org/10.1111/acel.70079) — is that PDI can also move into the nucleus, or control centre of the cell. It’s here it can play a vital role in repairing one of the most dangerous types of DNA damage, namely ‘double-strand breaks’.

“Until now, we didn’t know why PDI sometimes appeared in the nucleus,” Shadfar explained. “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.” This glue-like action was demonstrated in the research by stimulating DNA damage in the lab, both in human cancer cells and mouse brain cells. The cells struggled to repair themselves when PDI was removed, while DNA repair improved when PDI was added back in.

Live zebrafish were also tested, where the researchers found that boosting PDI production helped protect the animals from age-related DNA damage. Previously, cancer research has shown that PDI is not always positive — Shadfar likening it to “a double agent”. “In healthy cells,” Shadfar said, “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.”

Dr Shadfar, pictured, and the Motor Neuron Disease Research Centre team are using gene therapies, including the same technology used in COVID-19 vaccines, to target aging mechanisms that overlap with those found in motor neuron disease.

Any therapy that modulates PDI, therefore, will need to be precisely targeted to avoid unintended effects, with the next step for the researchers being gene therapy approaches to target aging mechanisms. “This work has the potential to transform how we approach neurodegenerative diseases,” Shadfar said. “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.”

This is an important goal given, as Shadfar explains, “[motor neuron disease] deaths have increased by 250% 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% each year.” And that, as Shadfar also points out: “By 2050, one in four Australians will be over 65.”

Top image credit: iStock.com/FG Trade Latin