There is no cure for Parkinson’s disease (PD), a progressive movement disorder that affects more than 10 million people worldwide. There is, however, a growing body of research driving experts toward unorthodox treatments. Case in point: On August 6, Researchers from the Broad Institute and Mass General Brigham published their study examining the impact of hypoxia — an absence of oxygen — on mice with Parkinson’s-like disease. The research suggests that low-oxygen air protects the brain, even going so far as to restore movement in the mice. Below is a summary of the research, which was published in Nature Neuroscience.
Low-Oxygen Air: A Boost for the Brain?
The August 6 study was the latest in a string of research involving hypoxia and mitochondrial disease. In fact, it builds on a decade of research, including numerous studies conducted by co-senior author Vamsi Mootha, into hypoxia’s strange ability to protect tissues from 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. “That raised the question: Could the same be true in more common neurodegenerative diseases like Parkinson’s?”
Mitochondrial Dysfunction in PD
Parkinson’s disease is not always classified as a mitochondrial disease. However, its symptoms can impact mitochondrial dysfunction. The disease leads to the progressive elimination of neurons in the brain, causing significant motor issues, including tremor, rigidity, bradykinesia, and akinesia. Affected neurons also accumulate toxic protein clumps called Lewy bodies, which have long been implicated in the function of the mitochondria. Additionally, the researchers write, “chemical inhibitors of mitochondrial complex I (MCI)… are toxic to midbrain dopaminergic neurons.” The loss of these neurons is a common PD pathology.
With this in mind, the researchers sought to discover whether hypoxia could minimize cellular dysfunction in people with PD. To do so, they turned to a mouse model of Parkinson’s in which mice are subjected to intrastriatal injection of α-synuclein preformed fibrils (PFFs), clumps of proteins that form the building blocks of Lewy bodies.
Impact of Low-Oxygen Air on PD Mouse Models
The researchers split the mice into two groups: one group breathing normal air with about 21 percent oxygen, and the other breathing air with about 11 percent oxygen. The low-oxygen air was comparable to conditions at high altitudes of about 4,800 meters above sea level. (For the sake of comparison, the city of Cusco, Peru, nestled within the Andes Mountains, is about 3,400 meters above sea level.)
The mice were assessed 12 weeks after receiving the PFF injections. The researchers used the pole, cage hang, and open field tests to measure motor function and behavior. “The pole test models motor coordination and bradykinesia,” wrote the team, “The cage hang test (also known as the wire hang test) measures muscle strength and endurance. The open field test (OFT) assesses anxiety-like behavior.”
The mice breathing normal air showed high levels of Lewy bodies and dead neurons, as well as severe movement problems. The mice that had breathed low-oxygen air, however, did not lose any neurons. And while they did develop Lewy bodies, they showed no signs of movement problems. In other words, hypoxia may not have halted the formation of Lewy bodies, but it did protect the neurons from their damaging effects.
Restoring Motor Function for Better PD Outcomes
While further research is needed before these results may translate to treatments, the study is promising. Especially exciting were the results about restored motor function. The researchers found that hypoxia reduces the impact of Parkinson’s-like disease on the mice even after they started showing symptoms, helping their motor skills rebound.
“The fact that we actually saw some reversal of neurological damage is really exciting,” said Mootha. “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.”
While still early, this research could point to a new way of treating PD without targeting α-synuclein or Lewy bodies, two of the more common treatment targets. “The results raise the possibility of an entirely new paradigm for addressing Parkinson’s disease,” said co-senior author Fumito Ichinose.
To study Parkinson’s disease, Scantox Neuro provides research in various preclinical in vivo PD models, including induced models by injecting PFFs (as used in the study presented above), MPTP, 6-OHDA, or rotenone as well as transgenic models such as the Line 61, hA53Ttg mouse models, LRRK2 G2019S rat model, and many more. All models can be used for efficacy studies and be evaluated for PD-like symptoms and pathology by behavioral, biochemical, and histological analyses. Furthermore, preclinical in vitro models to study PD are available that include models of lesion-induced neurotoxicity and mitochondrial impairment, as well as α-synuclein aggregation, seeding, and autophagy. Please contact us if you can’t find what you are looking for, as we constantly develop new in vitro and in vivo models to evaluate the efficacy of new PD drugs.
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