摘要：Scientists at the Broad Institute and Mass General Brigham have discovered that placing mice with Parkinson’s-like disease in a lo

Low-oxygen air both prevented and reversed symptoms in a mouse model of Parkinson’s disease.

低氧空气既能预防，也能逆转帕金森病小鼠模型中的症状。

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.

布罗德研究所和麻省总医院布莱根医疗系统的科学家发现，将患有帕金森样疾病的小鼠置于低氧环境中（类似珠穆朗玛峰大本营的空气），能够保护脑细胞，甚至恢复运动能力。

The study, published in Nature Neuroscience, indicates that in Parkinson’s, faulty cellular processes cause excess oxygen molecules to build up in the brain.

这项发表在《自然·神经科学》的研究表明，在帕金森病中，异常的细胞过程会导致大脑中积聚过量的氧分子。

This surplus oxygen appears to drive neurodegeneration, and limiting oxygen intake may help slow or even reverse symptoms.

这种过量的氧似乎会推动神经退行性病变，而限制氧气摄入可能有助于减缓甚至逆转症状。

“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.

“我们实际上看到了部分神经损伤的逆转，这真的令人振奋。”该研究的共同资深作者Vamsi Mootha说道。他是布罗德研究所的成员、哈佛医学院系统生物学与医学教授，同时也是霍华德·休斯医学研究所的研究员，任职于麻省总医院分子生物学系，该医院是麻省总医院布莱根医疗系统的创始成员之一。

“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.”

“这告诉我们存在一个‘治疗窗口’，在此期间某些神经元功能异常但尚未死亡——如果我们足够早进行干预，就能恢复它们的功能。”

“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.

“这些结果提出了一个全新的治疗帕金森病的范式的可能性。”该研究的另一位共同资深作者、市野文人补充道，他是哈佛医学院和麻省总医院的William T. G. Morton麻醉学教授。

Although the findings are promising, the team Stresses that it is far too early to apply them directly to patient care.

尽管研究结果令人鼓舞，但研究团队强调，现在直接将其应用于临床护理还为时过早。

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.

他们警告称，在没有医疗监督的情况下吸入低氧空气，尤其是以间歇模式（如仅在睡眠时）进行，可能有害，甚至可能加速疾病进展。

Even so, the researchers are hopeful that their work could eventually lead to drugs designed to safely reproduce the protective effects of low oxygen.

尽管如此，研究人员仍然希望他们的研究最终能促成药物的开发，从而安全地再现低氧的保护作用。

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.

该研究基于Mootha及其他人十年来对缺氧的研究——即身体或组织中的氧含量低于正常水平——以及其意外的抗线粒体疾病保护作用。

“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.

“我们最初发现，低氧能够缓解一些罕见疾病中与大脑相关的症状，这些疾病中线粒体受损，例如Leigh综合征和Friedreich共济失调，”领导布罗德Friedreich共济失调加速器的Mootha说道。

“That raised the question: Could the same be true in more common neurodegenerative diseases like Parkinson’s?”

“这引出了一个问题：在更常见的神经退行性疾病如帕金森病中，这种方法是否同样有效？”

Eizo Marutani, an instructor of anesthesia at MGH and Harvard Medical School, is the first author of the new paper.

Eizo Marutani是麻省总医院及哈佛医学院的麻醉学讲师，同时也是该新论文的第一作者。

A long-standing link

长期存在的关联

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.

帕金森病影响全球超过一千万人，导致大脑神经元逐渐丧失，引起震颤和动作迟缓。

Neurons affected by Parkinson’s also gradually accumulate toxic protein clumps called Lewy bodies.

帕金森病受影响的神经元还会逐渐积累称为路易小体的有毒蛋白团块。

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.

一些生化证据表明，这些蛋白团块会干扰线粒体功能——线粒体是细胞内微小的能量工厂，而Mootha知道它们在其他可通过缺氧治疗的疾病中会发生改变。

Moreover, anecdotally, people with Parkinson’s seem to fare better at high altitudes.

此外，据个别报道，帕金森患者在高海拔地区似乎状况更好。

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.

长期吸烟者体内一氧化碳水平升高，导致组织中氧含量减少，他们患帕金森病的风险似乎也更低。

“Based on this evidence, we became very interested in the effect of hypoxia on Parkinson’s disease,” said Ichinose.

“基于这些证据，我们对缺氧对帕金森病的影响产生了浓厚兴趣，”Ichinose说道。

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.

Mootha和Ichinose采用了一个成熟的帕金森小鼠模型，在该模型中，动物被注射α-突触核蛋白团块，以诱导路易小体的形成。

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.

随后，小鼠被分为两组：一组呼吸正常空气（21%氧气），另一组持续置于含11%氧气的密闭舱中——相当于生活在约16,000英尺（4,800米）的高海拔环境。

A new paradigm for Parkinson’s

帕金森病的新治疗范式

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.

结果令人震惊。注射α-突触核蛋白三个月后，呼吸正常空气的小鼠体内路易小体水平升高，神经元死亡，运动障碍严重。

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.

从一开始呼吸低氧空气的小鼠没有神经元丧失，也未表现出运动问题，尽管它们体内路易小体丰富。

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.

研究发现，缺氧并未阻止路易小体的形成，但却保护了神经元免受这些蛋白团块的损伤——Ichinose表示，这可能暗示了一种无需直接靶向α-突触核蛋白或路易小体的帕金森治疗新模式。

What’s more, when hypoxia was introduced six weeks after the injection, when symptoms were already appearing, it still worked.

更重要的是，在注射六周后，当症状已经出现时引入缺氧，它依然有效。

The mice’s motor skills rebounded, their anxiety-like behaviors faded, and the loss of neurons in the brain stopped.

小鼠的运动能力恢复，焦虑样行为消失，大脑神经元丧失停止。

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.

为了进一步探究潜在机制，团队分析了小鼠的大脑细胞，发现患帕金森症状的小鼠在大脑某些区域的氧含量远高于对照组和呼吸低氧空气的小鼠。

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.

研究人员表示，这种过量氧气可能源于线粒体功能障碍。受损的线粒体无法有效利用氧气，导致氧气积累到有害水平。

“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.”

“脑内过量氧气是有毒的，”Mootha说道，“通过减少整体氧气供应，我们切断了这种损伤的‘燃料’。”

Hypoxia in a pill

药丸形式的缺氧治疗

More work is needed before the findings can be directly used to treat Parkinson’s.

在将这些发现直接用于帕金森治疗之前，还需要更多研究。

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.

与此同时，Mootha及其团队正在开发“药丸形式的缺氧”药物，以模拟低氧效果，潜在用于治疗线粒体疾病，他们认为类似方法可能对某些类型的神经退行性疾病有效。

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.

虽然并非所有神经退行性模型都对缺氧有反应，但这一方法已在帕金森、Leigh综合征、Friedreich共济失调及加速衰老的小鼠模型中显示成功。

“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.”

“这可能并非所有神经退行性疾病的治疗方法，”Mootha表示，“但这是一个强有力的概念——可能改变我们对部分疾病的治疗思路。”

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精选词汇

【symptom】/ˈsɪmptəm/ n. a physical or mental sign indicating a condition or disease 症状

例句：Fatigue is often the first symptom of illness.

译文：疲劳通常是疾病的首要症状。

【restore】/rɪˈstɔːr/ v. to bring back to an earlier or original condition 恢复；修复

例句：The therapy restored her ability to walk.

译文：这种疗法恢复了她的行走能力。

【neurodegeneration】/ˌnjʊroʊdɪˌdʒɛnəˈreɪʃən/ n. progressive loss of structure or function of neurons 神经退行性变

例句：Neurodegeneration is the hallmark of Alzheimer’s disease.

译文：神经退行性变是阿尔茨海默病的标志。

【intervene】/ˌɪntərˈviːn/ v. to step in to alter a course of events 干预；介入

例句：Doctors must intervene early to prevent complications.

译文：医生必须及早干预以防并发症。

【dysfunctional】/dɪsˈfʌŋkʃənəl/ adj. not operating normally or properly 功能失调的

例句：The patient’s dysfunctional neurons caused motor impairment.

译文：患者功能失调的神经元导致了运动障碍。

【paradigm】/ˈpærədaɪm/ n. a model or pattern for something 范式；模式

例句：The study introduces a new paradigm for cancer treatment.

译文：该研究提出了一种癌症治疗的新范式。

【accelerate】/əkˈsɛləˌreɪt/ v. to cause something to move faster 加速

例句：Stress can accelerate the progression of disease.

译文：压力会加速疾病进展。

【supervision】/ˌsuːpərˈvɪʒən/ n. the act of overseeing 监督；管理

例句：Children require adult supervision while swimming.

译文：儿童游泳时需要成人监督。

【promising】/ˈprɑːmɪsɪŋ/ adj. showing signs of success or improvement 有前景的

例句：The drug is still experimental but very promising.

译文：该药物仍处于实验阶段，但前景非常乐观。

【hypoxia】/haɪˈpɑːksiə/ n. a condition of insufficient oxygen 缺氧

例句：Hypoxia can cause severe brain damage if untreated.

译文：如果不治疗，缺氧可能导致严重脑损伤。

【protective】/prəˈtɛktɪv/ adj. intended to keep safe or defend 保护性的

例句：The helmet provides protective benefits for cyclists.

译文：头盔为骑行者提供保护作用。

【mitochondrial】/ˌmaɪtəˈkɑːndrɪəl/ adj. relating to mitochondria 线粒体的

例句：Mitochondrial dysfunction is linked to many diseases.

译文：线粒体功能障碍与多种疾病相关。

【surplus】/ˈsɜːrpləs/ adj./n. more than what is needed 过剩的；过量

例句：Surplus oxygen in the brain can be harmful.

译文：大脑中过量的氧可能有害。

【reproduce】/ˌriːprəˈduːs/ v. to copy or recreate something 再现；复制

例句：The experiment reproduced the protective effect in animals.

译文：实验在动物体内再现了保护作用。

【molecule】/ˈmɑːlɪˌkjuːl/ n. a group of atoms bonded together 分子

例句：Water is composed of two hydrogen molecules and one oxygen molecule.

译文：水由两个氢分子和一个氧分子组成。

【founding】/ˈfaʊndɪŋ/ adj. related to the beginning or establishment 创始的；建立的

例句：He is a founding member of the research institute.

译文：他是该研究所的创始成员之一。

【viability】/ˌvaɪəˈbɪləti/ n. ability to survive or work 可行性；生存能力

例句：The viability of neurons depends on oxygen supply.

译文：神经元的生存依赖于氧气供应。

【anesthesia】/ˌænəsˈθiːʒə/ n. medically induced loss of sensation 麻醉

例句：The patient was under general anesthesia during surgery.

译文：患者在手术中接受了全身麻醉。

【clinical】/ˈklɪnɪkəl/ adj. relating to medical treatment 临床的

例句：Clinical trials are necessary before new drugs are approved.

译文：新药物在获批前必须进行临床试验。

【disorder】/dɪsˈɔːrdər/ n. an illness that affects normal function 疾病；紊乱

例句：Mitochondrial disorders often lead to muscle weakness.

译文：线粒体疾病常导致肌肉无力。

【intake】/ˈɪnteɪk/ n. the amount of something taken in 摄入

例句：Limiting sugar intake reduces risk of diabetes.

译文：限制糖摄入可降低糖尿病风险。

【surveillance】/sərˈveɪləns/ n. close observation 监测；监管

例句：The trial requires strict medical surveillance.

译文：该试验需要严格的医疗监测。

【reversal】/rɪˈvɜːrsəl/ n. a change to an opposite condition 逆转；反转

例句：The drug showed a reversal of disease progression.

译文：药物显示出疾病进展的逆转。

【impairment】/ɪmˈpɛrmənt/ n. weakened or damaged condition 损伤；障碍

例句：Memory impairment is common in dementia patients.

译文：记忆障碍在痴呆患者中很常见。

【dysfunction】/dɪsˈfʌŋkʃən/ n. abnormal or impaired function 功能障碍

例句：Dysfunction of mitochondria leads to energy deficits.

译文：线粒体功能障碍导致能量不足。

【institute】/ˈɪnstɪˌtuːt/ n. an organization for education or research 研究所；机构

例句：The Broad Institute is a leader in genetic research.

译文：布罗德研究所是遗传学研究的领军机构。

【investigator】/ɪnˈvɛstəˌɡeɪtər/ n. a person who conducts research or inquiry 研究人员；调查员

例句：He is a principal investigator of the project.

译文：他是该项目的首席研究员。

【excess】/ɪkˈsɛs/ adj./n. more than is necessary or allowed 过量的；过剩

例句：Excess oxygen accelerates cell damage.

译文：过量的氧会加速细胞损伤。

【viable】/ˈvaɪəbl/ adj. capable of working successfully 可行的；能生存的

例句：The plan is viable only with proper funding.

译文：该计划只有在有适当资金支持时才可行。

【alleviate】/əˈliːvieɪt/ v. to make something less severe 缓解；减轻

例句：The drug helps alleviate chronic pain.

译文：这种药物有助于缓解慢性疼痛。

【mitochondria】/ˌmaɪtəˈkɑːndriə/ n. the cell’s energy-producing organelles 线粒体

例句：Mitochondria generate ATP, the energy currency of the cell.

译文：线粒体生成ATP，即细胞的能量货币。

【rare】/rer/ adj. uncommon or unusual 罕见的

例句：Leigh syndrome is a rare genetic disorder.

译文：Leigh综合征是一种罕见的遗传疾病。

【neurodegenerative】/ˌnjʊroʊdɪˈdʒɛnərətɪv/ adj. relating to progressive loss of neuronal function 神经退行性的

例句：Alzheimer’s is a neurodegenerative disorder.

译文：阿尔茨海默病是一种神经退行性疾病。

【instructor】/ɪnˈstrʌktər/ n. a teacher or lecturer 教员；讲师

例句：The instructor explained the surgical procedure in detail.

译文：讲师详细讲解了手术操作流程。

【progressive】/prəˈɡrɛsɪv/ adj. developing gradually 逐步的；渐进的

例句：Parkinson’s disease causes progressive motor decline.

译文：帕金森病导致运动能力逐步下降。

【accumulate】/əˈkjuːmjəˌleɪt/ v. to gather or build up 累积；堆积

例句：Toxic proteins accumulate in affected neurons.

译文：有毒蛋白在受影响的神经元中累积。

【toxic】/ˈtɑːksɪk/ adj. poisonous or harmful 有毒的；有害的

例句：Exposure to toxic chemicals can damage the liver.

译文：接触有毒化学物质会损伤肝脏。

【clump】/klʌmp/ n./v. a cluster or group 团块；聚集

例句：Protein clumps disrupt cellular function.

译文：蛋白团块破坏细胞功能。

【interfere】/ˌɪntərˈfɪr/ v. to hinder or obstruct 干扰；妨碍

例句：Medication can interfere with sleep patterns.

译文：药物可能干扰睡眠模式。

【mitochondrial dysfunction】/ˌmaɪtəˈkɑːndrɪəl dɪsˈfʌŋkʃən/ n. impaired mitochondrial function 线粒体功能障碍

例句：Mitochondrial dysfunction contributes to neurodegeneration.

译文：线粒体功能障碍会导致神经退行性变。

来源：纵观世界Max2023