The Secret Of Heights: Clues To Treating Parkinson's Come From The Thin Mountain Air

Parkinson's disease occurs when brain cells that produce dopamine, a substance essential for controlling movement, begin to die. Recent research shows that this process is linked to problems in mitochondria, which are the cells' "powerhouses." A curious study found that reducing the amount of oxygen in the air can protect these cells and even improve symptoms in animals with Parkinson's. This opens the possibility of new treatments using this mechanism to slow the disease in the future.

Parkinson's disease is a progressive neurological disorder that affects millions of people worldwide. It manifests primarily through motor symptoms, such as hand tremors, muscle stiffness, slow movement, and difficulty initiating actions, as well as postural instability that compromises balance.

However, the symptoms are not limited to the body. Many patients also suffer from sleep disturbances, mood swings, cognitive difficulties, and digestive problems. Therefore, the impact of the disease goes far beyond visible movements.

In the brain, the main characteristic of Parkinson's disease is the gradual loss of neurons that produce dopamine. These neurons are concentrated in a region called the substantia nigra, located in the midbrain, which is essential for controlling movement. In addition to the loss of these neurons, there is also the accumulation of abnormal structures within nerve cells, known as Lewy bodies and Lewy neurites.

These deposits are largely made up of a protein called alpha-synuclein. Although the normal role of this protein is not yet fully understood, it is known that when it clumps together into fibrils, it can become toxic to nerve cells, primarily damaging mitochondria.

Mitochondria function as cellular "powerhouses," responsible for generating most of the energy needed for brain function. In Parkinson's disease, alpha-synuclein in its abnormal form interferes with the function of Complex I, an essential part of mitochondria.

This blockage impairs energy production, fragments mitochondria, alters nutrient transport, and increases the production of aggressive molecules called reactive oxygen species.

These excess molecules cause oxidative stress, gradually weakening and destroying dopamine-producing neurons. It's no coincidence that chemicals that block Complex I, such as pesticides and some synthetic compounds, can cause symptoms similar to Parkinson's in humans and animals.

Research with animal models reinforces this link. Genetically modified mice that lose proper Complex I function develop symptoms similar to Parkinson's. This shows that mitochondrial malfunction is not just a consequence of the disease, but may be at its root.

Unfortunately, to date, there is no treatment capable of halting or reversing this degeneration; available medications only alleviate the symptoms.

Interestingly, animal studies have yielded an unexpected discovery: reducing oxygen levels can protect neurons. This is because so-called hypoxia, or exposure to air with less oxygen, appears to reduce the damage caused by mitochondrial dysfunction.

In mice with mutations that mimic a serious mitochondrial disease called Leigh syndrome, keeping the animals in environments with lower oxygen concentrations not only slowed neurodegeneration but even increased their lifespan fivefold. And more surprisingly, even in advanced stages, hypoxia was able to halt and even reverse some of the degeneration.

In the specific case of Parkinson's disease, tests on mice showed that continuous exposure to reduced oxygen levels protected dopamine-producing neurons and prevented loss of movement.

When these animals were exposed to alpha-synuclein fibrils, which normally accelerate neuronal death, those breathing normal oxygen concentration (21%) developed motor symptoms and brain damage. Those breathing air with less oxygen (11%) were protected: their neurons survived, and the same level of degeneration did not occur.

Furthermore, when oxygen deprivation began weeks after the onset of the disease, motor symptoms improved and the progression of degeneration was halted.

Number of dopaminergic neurons (TH+) in the substantia nigra pars compacta (SNpc) in mice treated with α-syn monomer or preformed α-syn fibrils (PFF) for 12 weeks, under normal oxygen conditions (breathing 21% oxygen) and lower oxygen conditions (breathing 11% oxygen).

These results have also been observed in much simpler organisms, such as the worm Caenorhabditis elegans, suggesting that this effect of lower-oxygen air is conserved throughout evolution.

There are also reports of Parkinson's patients who report experiencing a spontaneous improvement in symptoms when traveling to high altitudes, where the amount of naturally available oxygen is lower. Although these reports are isolated observations, they reinforce the idea that hypoxia can be explored as a form of treatment.

In summary, the latest findings indicate that controlled oxygen reduction may have a protective effect on the brain in neurodegenerative conditions. In the case of Parkinson's disease, this opens up a fascinating possibility: that even after the onset of symptoms, hypoxia could help preserve neurons and improve patients' quality of life.

Although many human studies are still needed to confirm the safety and efficacy of this strategy, this line of research may represent an innovative path to combat one of today's most challenging neurological diseases.

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Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease

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

Nature Neuroscience. 6 August 2025

DOI: 10.1038/s41593-025-02010-4

Abstract: 

Parkinson’s disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.