A study from researchers from the Broad Institute of MIT and Harvard and Mass General Brigham has shown that continuous exposure to low-oxygen air to create hypoxia protects against neurodegeneration and restores movement in a mouse model of Parkinson’s disease (PD). The findings, published in Nature Neuroscience, offer a potential new therapeutic strategy that could prevent or even reverse the progression of PD by limiting oxygen availability to the brain.
“The fact that we actually saw some reversal of neurological damage is really exciting,” said co-senior author Vamsi Mootha, MD, an institute member at the Broad and a professor at Harvard Medical School. “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 current research builds on a decade of findings by Mootha and other investigators into hypoxia, or lower-than-normal oxygen levels in the body and its tissues. Patients with PD have anecdotally reported symptom improvement at high altitudes, and heavy smoking, which can reduce oxygen delivery due to elevated carbon monoxide, has also been linked to lower PD risk.
Research in other rare neurodegenerative disorders such as Leigh syndrome and Friedreich’s ataxia has also implicated hypoxia as protective against the mitochondrial disruption that cause these diseases. “Based on this evidence, we became very interested in the effect of hypoxia on Parkinson’s disease,” said co-senior author Fumito Ichinose, MD, a professor of anesthesia at Harvard Medical School and MGH.
To find the effects hypoxia may have, the team used a well-established mouse model of PD. Mice were injected with preformed fibrils (PFFs) of α-synuclein, which leads to aggregation of Lewy bodies and subsequent neurodegeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). One group of mice was housed in normal oxygen conditions (21%), and the other in continuous low-oxygen conditions (11%), comparable to high-altitude environments around 4,800 meters.
Data from this experiment showed that mice breathing normal air developed high levels of Lewy bodies, loss of dopaminergic neurons, and severe motor dysfunction. In contrast, mice exposed to low-oxygen conditions from the start did not lose neurons and showed no signs of movement impairment.
The team also sought to understand the effects of a low-oxygen environment in mice who already exhibited symptoms of PD and neuron loss, introducing them to that environment six weeks after the PFF injection. In these mice the progression of neurodegeneration halted, motor skills improved, and anxiety-like behaviors diminished.
“These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes,” the researchers wrote.
The researchers noted that hypoxia did not prevent α-syn aggregation. Rather, it appeared to protect neurons from the toxic effects of these aggregates. Tissue analysis showed that mice with PD-like symptoms under normal oxygen had excess oxygen levels in brain regions, consistent with mitochondrial dysfunction and impaired oxygen utilization. Damaged mitochondria fail to consume oxygen efficiently, resulting in tissue hyperoxia.
“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.”
The researchers hypothesize that reducing oxygen levels may protect neurons by both directly lowering tissue hyperoxia and indirectly activating hypoxia-inducible factor (HIF)-dependent pathways, which reduce lipid peroxidation and protect mitochondrial function. RNA sequencing and proteomic analysis of substantia nigra tissue revealed strong upregulation of HIF target genes such as Ldha, Slc16a3, and Ndufa4l2 in the low-oxygen-treated mice. “Our data support the notion that both HIF-dependent and HIF-independent mechanisms may be at play in conferring the observed neuroprotection,” the researchers wrote.
The team noted their study’s limitations, including that analyses were conducted on the entire substantia nigra region rather than isolating the SNpc and its dopaminergic neurons. They also said that longer follow-up studies are needed to examine additional pathological changes and assess effects in aging models.
At present, the findings are not directly translatable to human patients and the investigators strongly discourage unsupervised exposure to low-oxygen environments. Unsupervised or intermittent hypoxia can be dangerous and might worsen disease. However, the investigators noted that efforts are currently underway to develop “hypoxia in a pill” drugs, targeted at other mitochondrial disorders, that mimic the neuroprotective effects of low-oxygen exposure without the risks.
“It may not be a treatment for all types of neurodegeneration,” Mootha said, “but it’s a powerful concept—one that might shift how we think about treating some of these diseases.”
