“A 60-year-old worker fell eight feet from a pile of rubber, landing on his hips and shoulders, and striking his head on the concrete floor. He was dazed for a few minutes but was able to get up without assistance. However, while walking upstairs to the dressing room, he noticed that he was unable to raise his left foot. Later, while riding home and while eating dinner, he tripped and stumbled on one side. He died two and a half years later. Autopsy revealed noticeable neural loss and iron accumulation in substantia nigra–the brain part severely affected in Parkinson’s disease.” – Bruetsch and DeArmond, 1935.
It would eventually come to light that the worker’s fall had sped up the progression of his previously undiagnosed Parkinsonism, a broader term for conditions that mimic Parkinson’s disease, including tremors, stiffness, and balance issues. Unlike classic Parkinson’s disease, which arises from gradual neurodegeneration, this man’s symptoms likely stemmed from trauma-induced brain damage. After he died, Bruetsch and DeArmond found that his substantia nigra showed clear signs of neural loss and iron buildup. As part of the brain that controls movements, damage to the substantia nigra manifests as Parkinsonian symptoms.
That was not the first time iron was found in the brain of an individual suffering from Parkinsonism. A decade earlier, German physicians Hallervorden and Spatz found similar iron deposits in the substantia nigra of a 24-year-old woman who had severe Parkinsonian symptoms before her death. Unlike the injured worker, her condition was genetic, and is now called pantothenate kinase-associated neurodegeneration—a type of neurodegeneration with brain iron accumulation. These inherited diseases cause iron to accumulate in the basal ganglia where the substantia nigra is located, leading to movement disorders, dementia, and other neurological issues.
For decades, the role of iron in Parkinson’s disease remained overlooked—not because it was irrelevant, but because scientists lacked the tools and prior studies to study it effectively. Instead, research efforts were directed toward alpha-synuclein plaques, misfolded protein clumps also found in the brains of Parkinson’s patients. Proteins were easier to analyze; detection methods had existed since the 1950s, whereas technology to study metals in the brain only emerged in the 1990s.
Today, advanced imaging techniques like magnetic resonance imaging (MRI) allow researchers to measure iron levels in living brains. This technology enables scientists to study iron distribution in the brain and, most importantly, how iron accumulates in the brain. Knowing the answers to this set of questions is a step closer to cracking down on how and why iron can cause Parkinson’s disease.
Iron accumulates in aging brains
Despite its bad reputation, iron is vital for our health, especially for the brain. This unique metal can shift between two ionic forms, Fe2+ and Fe3+, playing essential roles in energy production and oxygen transport. But like an unattended crayon in the hands of a toddler, free iron ions can wreak havoc, causing damage across delicate cellular structures. To prevent chaos, our bodies employ a strict security system: specialized proteins that bind and safely store iron, ensuring it does not react uncontrollably with other molecules.
Scientists made a startling discovery when they measured brain iron levels across different ages. From young adults in their 20s to seniors in their 80s, one trend stood out: the older we get, the more iron builds up in our brains. Interestingly, this excess iron piles up in the basal ganglia, the very same brain region that deteriorates in Parkinson’s disease. This means that the shaky hands, stiff muscles, and movement struggles in the elderly might not just be ‘normal aging’, but could also be linked to the iron buildup in the brain.
Increased brain iron levels during aging can be attributed to changes in various proteins that regulate iron metabolism. One of the culprits is hepcidin, a regulator of iron exporter ferroportin, whose levels increase with age and inflammation. Typically, when our bodies encounter invading pathogens, they send out a danger signal in the form of inflammation. Since pathogens steal iron from us to support their growth, our bodies protect our iron by ramping up hepcidin production. Hepcidin then degrades ferroportin, preventing iron from leaking out of the cells.
However, inflammation can also arise as a side product of aging. As we age, many things can go wrong. First, cells accumulate damage and can become senescent, where they stop dividing but remain metabolically active, producing molecules that contribute to tissue inflammation and damage. Second, immune cells shift towards a pro-inflammatory state, leading to an overactive inflammatory response. Lastly, our body’s natural defenses against oxidative stress may weaken as we age, leading to the accumulation of damage and further contributing to inflammation.
All these factors cause increased hepcidin production, which in turn prevents iron export from cells, resulting in cells becoming overloaded with iron. Since the brain is the most iron-hungry organ, the effect of inflammaging on iron levels is especially prominent in the brain.
While the reason why iron accumulates in the basal ganglia is still unknown, the aging process creates an environment that disrupts the delicate balance of iron regulation. This in turn contributes to the progression of age-related neurodegenerative diseases like Parkinson’s, and Alzheimer’s.
Iron causes age-related neurodegeneration
While iron naturally accumulates in the brain with age, Parkinson’s and Alzheimer’s patients show significantly higher iron levels than their healthy peers—a difference too stark to attribute to normal aging alone.
For decades, scientists like Professor Ashley Bush at the University of Melbourne have pursued this mystery, focusing on a critical question: What other factors cause free iron to accumulate in patients with Parkinson’s and Alzheimer’s disease? The answer, it turns out, lies in the very proteins that define these disorders.
Bush’s work revealed the dangerous effects of two notorious protein clumps in Alzheimer’s and Parkinson’s—beta amyloid and alpha-synuclein (Figure 2)—on iron regulation machinery. First, they chemically transform iron into its more reactive Fe2+ form, essentially turning iron into a weapon. Then, they disable the brain’s iron regulation mechanism, trapping neurons in a nightmare scenario: iron floods in, but the cells cannot stop absorbing it. This excess iron not only damages neurons but also accelerates the clumping of the very proteins that cause the problem in the first place. The result is a self-destructive loop: more protein clumps, more trapped iron, and irreversible damage.
Difference between normal vs Alzheimer’s neurons. Alzheimer’s neurons have beta-amyloid protein clumps, which can team up with iron to exacerbate damage.
But how exactly does too much iron kill neurons?
In 2012, Brent Stockwell and his team first proposed the concept of ferroptosis—an iron-dependent and distinct form of cell death marked by the accumulation of reactive oxygen species (ROS). At low levels, ROS plays beneficial roles, but in excess, it acts like tiny fireballs, damaging cellular components. One of their primary targets is lipids in the cell membrane, which they transform into toxic lipid peroxides. Normally, antioxidants act as firefighters, neutralizing ROS before they cause harm. However, during ferroptosis, these defenses fail, leaving ROS to rage unchecked. The result is catastrophic: the cell membrane ruptures, causing the cell to burst like a balloon—a process known as cell death.
This destructive process is particularly relevant in neurodegenerative diseases like Parkinson’s, where iron buildup worsens neuronal damage. As neurons die, they release stored iron from within the cells, which then triggers more ferroptosis in neighboring cells. Crucially, Stockwell’s team demonstrated that this cycle can be interrupted. By using iron chelators—drugs that bind and remove excess iron—they were able to suppress ferroptosis, confirming iron’s central role in driving this lethal cascade.
Thanks to this work, the scientific community now recognizes that disrupted metal homeostasis may be a root cause, not just a side effect, of neurodegeneration. While much remains to be explored, one thing is clear: the “rusty brain” can no longer be ignored.
What’s next?
Despite 1.1 million Americans living with Parkinson’s today, we still lack a cure. The discovery of iron’s role in neurodegeneration has opened an exciting new frontier in treatment.
When I began my PhD seven years ago, this promising lead drew me to join a lab that had just developed a groundbreaking new class of iron-regulating drugs. Unlike traditional iron chelators that bind iron in the blood, this innovative drug acts like cellular iron traffic controllers—shuttling iron in or out of cells depending on where it is needed most.
What makes this approach so revolutionary is its braking system. The drug automatically stops working once a proper iron balance is achieved, preventing the undesirable side effects of taking too much iron from neurons, which is a common side effect of iron chelators. Remember how vital iron is for brain function? A recent clinical trial showed that iron chelators caused a brain iron shortage in Parkinson’s patients, which further worsened the disease symptoms.
This breakthrough represents more than just another medication—it is a paradigm shift in how we understand and treat neurodegeneration. While there is still work ahead to bring this therapy to patients, for the first time, we can envision a future where we can potentially stop Parkinson’s disease in its tracks.
Author-
Stella Ekaputri is a scientific writer at City of Hope. Before moving into science communication and writing, she was a postdoctoral researcher at Caltech. There, she studied how the gut microbiome affects the immune system in Parkinson’s disease. She earned her PhD from the University of Illinois at Urbana-Champaign, where she explored how iron imbalance contributes to Parkinson’s disease using chemical biology probes. She now aims to educate and share stories through her writing. A dreamer and thinker, she enjoys spending her free time reading about science, psychology, and philosophy. She also loves running, cycling, and spending time in nature.
Editors-
Ananya Sen and Roopsha Sengupta
Images-
Cover image- created on Canva
Inset image- Sarina Mehta (Author) | Copyright © 2024 Sarina Mehta | Licensed under CC BY-NC-ND 4.0.
