Low-oxygen air both prevented and reversed symptoms in a mouse model of Parkinson’s disease.
Scientists at the Broad Institute and Mass General Brigham have discovered that placing mice with Parkinson’s-like disease in a low-oxygen environment, similar to the air at Mount Everest base camp, can protect brain cells and even restore movement.
The study, published in Nature Neuroscience, indicates that in Parkinson’s, faulty cellular processes cause excess oxygen molecules to build up in the brain. This surplus oxygen appears to drive neurodegeneration, and limiting oxygen intake may help slow or even reverse symptoms.
“The fact that we actually saw some reversal of neurological damage is really exciting,” said co-senior author Vamsi Mootha, an institute member at the Broad, professor of systems biology and medicine at Harvard Medical School, and a Howard Hughes Medical Institute investigator in the Department of Molecular Biology at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system. “It tells us that there is a window during which some neurons are dysfunctional but not yet dead — and that we can restore their function if we intervene early enough.”
“The results raise the possibility of an entirely new paradigm for addressing Parkinson’s disease,” added co-senior author Fumito Ichinose, the William T. G. Morton professor of anesthesia at Harvard Medical School and MGH.
Although the findings are promising, the team stresses that it is far too early to apply them directly to patient care. They warn that breathing low-oxygen air without medical supervision, particularly in intermittent patterns such as only during sleep, can be harmful and may even accelerate the disease. Even so, the researchers are hopeful that their work could eventually lead to drugs designed to safely reproduce the protective effects of low oxygen.
The study builds on a decade of research from Mootha and others into hypoxia — the condition of having lower than normal oxygen levels in the body or tissues — and its unexpected ability to protect against mitochondrial disorders.
“We first saw that low oxygen could alleviate brain-related symptoms in some rare diseases where mitochondria are affected, such as Leigh syndrome and Friedreich’s ataxia,” said Mootha, who leads the Friedreich’s Ataxia Accelerator at Broad. “That raised the question: Could the same be true in more common neurodegenerative diseases like Parkinson’s?”
Eizo Marutani, an instructor of anesthesia at MGH and Harvard Medical School, is the first author of the new paper.
A long-standing link
Parkinson’s disease, which affects more than 10 million people worldwide, causes the progressive loss of neurons in the brain, leading to tremors and slowed movements. Neurons affected by Parkinson’s also gradually accumulate toxic protein clumps called Lewy bodies. Some biochemical evidence has suggested that these clumps interfere with the function of mitochondria — the tiny powerhouses of the cell that Mootha knew were altered in other diseases that could be treated with hypoxia.
Moreover, anecdotally, people with Parkinson’s seem to fare better at high altitudes. And long-term smokers — who have elevated levels of carbon monoxide, leading to less oxygen in tissues — also appear to have a lower risk of developing Parkinson’s.
“Based on this evidence, we became very interested in the effect of hypoxia on Parkinson’s disease,” said Ichinose.
Mootha and Ichinose turned to a well-established mouse model of Parkinson’s in which animals are injected with clumps of the α-synuclein proteins that seed the formation of Lewy bodies. The mice were then split into two groups: one breathing normal air (21 percent oxygen) and the other continuously housed in chambers with 11 percent oxygen — comparable to living at an altitude of about 16,000 feet or 4,800 meters.
A new paradigm for Parkinson’s
The results were striking. Three months after receiving α-synuclein protein injections, the mice breathing normal air had high levels of Lewy bodies, dead neurons, and severe movement problems. Mice that had breathed low-oxygen air from the start didn’t lose any neurons and showed no signs of movement problems, despite developing abundant Lewy bodies.
The findings show that hypoxia wasn’t stopping the formation of Lewy bodies but was protecting neurons from the damaging effects of these protein clumps — potentially suggesting a new mode of treating Parkinson’s without targeting α-synuclein or Lewy bodies, Ichinose said.
What’s more, when hypoxia was introduced six weeks after the injection, when symptoms were already appearing, it still worked. The mice’s motor skills rebounded, their anxiety-like behaviors faded, and the loss of neurons in the brain stopped.
To further explore the underlying mechanism, the team analyzed brain cells of the mice and discovered that mice with Parkinson’s symptoms had much higher levels of oxygen in some parts of the brain than control mice and those that had breathed low-oxygen air. This excess oxygen, the researchers said, likely results from mitochondrial dysfunction. Damaged mitochondria can’t use oxygen efficiently, so it builds up to damaging levels.
“Too much oxygen in the brain turns out to be toxic,” said Mootha. “By reducing the overall oxygen supply, we’re cutting off the fuel for that damage.”
Hypoxia in a pill
More work is needed before the findings can be directly used to treat Parkinson’s. In the meantime, Mootha and his team are developing “hypoxia in a pill” drugs that mimic the effects of low oxygen to potentially treat mitochondrial disorders, and they think a similar approach might work for some forms of neurodegeneration.
While not all neurodegenerative models respond to hypoxia, the approach has now shown success in mouse models of Parkinson’s, Leigh syndrome, Friedreich’s ataxia, and accelerated aging.
“It may not be a treatment for all types of neurodegeneration,” said Mootha, “but it’s a powerful concept — one that might shift how we think about treating some of these diseases.”
Reference: “Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease” by Eizo Marutani, Maria Miranda, Timothy J. Durham, Sharon H. Kim, Dreson L. Russell, Presli P. Wiesenthal, Paul Lichtenegger, Marissa A. Menard, Charlotte F. Brzozowski, Haobo Li, Gary Ruvkun, Joshua D. Meisel, Laura Volpicelli-Daley, Vamsi K. Mootha and Fumito Ichinose, 6 August 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-02010-4
Support for the study was provided by the Marriott Foundation, the National Institutes of Health, the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, the National Institute of General Medical Sciences, the Deutsche Forschungsgemeinschaft, the Max Kade Foundation, and the Howard Hughes Medical Institute.
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