Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome
Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome
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DOI：
10.1073/pnas.1621511114
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发表时间：
2017-05-23
影响因子：
11.1
通讯作者：
Zapol, Warren M.
中科院分区：
文献类型：
--
作者：
Ferrari, Michele;Jain, Isha H.;Zapol, Warren M.
最常见的儿童线粒体疾病是Leigh综合征，这是一种发作性亚急性神经退行性疾病，可在生命的最初几年内导致死亡，目前尚无经证实的通用治疗方法。缺乏复合体I亚基Ndufs4的小鼠会发展为类似Leigh综合征的致命进行性脑病，并在大约60日龄时死亡。我们之前报道过，在这些小鼠中，从幼年开始持续呼吸标准浓度的11% O-2可以预防神经系统疾病，并显著提高生存率。在这里，我们报告三个进展。首先，我们报告了暴露于缺氧或高氧的Ndufs4 KO小鼠的最新生存曲线和器官病理。正常缺氧处理的KO小鼠在大约60天死于神经退行性变，缺氧处理的小鼠最终在大约270天死于心脏病，高氧处理的小鼠在几天内死于急性肺水肿。其次，我们报道更保守的低氧方案，如持续的17% O-2正压或间歇性低氧，在预防神经病理方面是无效的。最后，我们表明，在患有晚期脑病的小鼠中，正常呼吸11% O-2可以逆转其既定的神经系统疾病，这可以通过改善行为、循环疾病生物标志物和生存率来证明。重要的是，缺氧4周后，病理MRI脑病变和神经组织病理学结果逆转。在恢复正常缺氧后，Ndufs4 KO小鼠在几天内死亡。未来的工作需要确定缺氧是否可以用来预防和逆转其他动物模型中的神经变性，并确定它是否可以以一种安全实用的方式提供给医院内的人体治疗试验。
The most common pediatric mitochondrial disease is Leigh syndrome, an episodic, subacute neurodegeneration that can lead to death within the first few years of life, for which there are no proven general therapies. Mice lacking the complex I subunit, Ndufs4, develop a fatal progressive encephalopathy resembling Leigh syndrome and die at approximate to 60 d of age. We previously reported that continuously breathing normobaric 11% O-2 from an early age prevents neurological disease and dramatically improves survival in these mice. Here, we report three advances. First, we report updated survival curves and organ pathology in Ndufs4 KO mice exposed to hypoxia or hyperoxia. Whereas normoxia-treated KO mice die from neurodegeneration at about 60 d, hypoxia-treated mice eventually die at about 270 d, likely from cardiac disease, and hyperoxia-treated mice die within days from acute pulmonary edema. Second, we report that more conservative hypoxia regimens, such as continuous normobaric 17% O-2 or intermittent hypoxia, are ineffective in preventing neuropathology. Finally, we show that breathing normobaric 11% O-2 in mice with late-stage encephalopathy reverses their established neurological disease, evidenced by improved behavior, circulating disease biomarkers, and survival rates. Importantly, the pathognomonic MRI brain lesions and neurohistopathologic findings are reversed after 4 wk of hypoxia. Upon return to normoxia, Ndufs4 KO mice die within days. Future work is required to determine if hypoxia can be used to prevent and reverse neurodegeneration in other animal models, and to determine if it can be provided in a safe and practical manner to allow in-hospital human therapeutic trials.