Duke researchers may have found a path to treat a family of rare neurodegenerative disease called neurodegeneration with brain iron accumulation (NBIA). People with NBIA have extra iron accumulation in the basal ganglia – the part of the brain responsible for assisting in regular movements. The condition is progressive, and without a way to clear out the excess iron, symptoms continue to worsen, and survival after diagnosis is 10-12 years. Currently, there are no effective treatments and the exact disease mechanisms are not well understood.
A recent discovery by Jen-Tsan Ashley Chi, MD, PhD, professor in molecular genetics and microbiology, Chao-Chieh (Jerry) Lin, senior research associate, and team may offer hope for people with NBIA. They found that coenzyme A (CoA), a molecule that fuels cells, protects the brain from a form of iron-driven cell death called ferroptosis. Results were published in the Journal of Clinical Investigation.
“People with NBIA have trouble synthesizing coenzyme A,” Lin said, “which is linked to the iron accumulation in their brain.” CoA- is like a battery pack that fuels many of the body’s essential systems — including the brain’s defenses against cell damage.
Ferroptosis is a newly discovered form of regulated cell death that is triggered by iron and oxidative damage to cell membranes and is regulated by CoA.
“We found that defects in CoA make cells more prone to ferroptosis by disrupting mitochondrial defenses against oxidative stress through a new protein modification called CoAlation,” Chi said.
Our cells use special tags to turn proteins on or off, much like flipping switches to control their functions. The researchers discovered a new kind of tag, called CoAlation, where CoA attaches to mitochondrial proteins and helps protect cells from damage when iron levels are too high.
By boosting CoA, mimicking its protective effects, or using ferroptosis inhibitors, the team found they could stop or limit ferroptosis cell death. However, this CoA-mediated shield against ferroptosis becomes repaired when the CoA synthesis is disrupted in patients with mutations associated with NBIA.
Chi and team believe there’s potential that this newly discovered pathway could also be used to design other therapies for conditions, including cancer, where ferroptosis may be key. “This is just the start,” Lin said. “We’ve found a whole new way CoA can protect cells, and there’s still so much more to discover.”
By uncovering this hidden link between a vital cellular molecule and iron-triggered brain damage, these findings may pave the way for much-needed treatments for patients who currently have no effective options.