Autophagy is essential for mouse sense of balance
Autophagy is essential for mouse sense of balance
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DOI：
10.1172/jci42601
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Marino, Guillermo;Fernandez, Alvaro F.;Lopez-Otin, Carlos
自噬是一个进化上保守的过程，对真核生物的细胞内环境稳定和生物体生存能力至关重要。然而，它在生物体生理学和行为的高阶过程中的功能程度仍然未知。在这里，我们报告说，自噬是必不可少的维持平衡的小鼠和它的缺陷导致严重的平衡障碍。我们产生了自噬蛋白-1蛋白酶（Atg 4 b）缺陷的小鼠，并表明它们具有自噬活性的显著系统性降低。自噬减少通过自噬体组分LC 3及其旁系同源物的蛋白水解处理缺陷发生，这损害了自噬体成熟的速率。尽管它们的生存能力，Atg 4 b-null小鼠表现出不寻常的行为模式，这是内耳病理学的常见特征。与此一致，Atg 4 b基因敲除小鼠在耳石发育中表现出缺陷，耳石是平衡感（平衡感受）所必需的有机碳酸钙晶体。此外，这些异常在Atg 5（-/-）小鼠中加剧，Atg 5（-/-）小鼠完全缺乏进行自噬的能力，证实自噬活性是耳石生物发生所必需的。自噬缺陷还导致耳石核心蛋白的分泌和组装受损，从而阻碍耳石发育。总而言之，这些结果描述了自噬在内耳发育和平衡感受中的重要作用，并为理解和治疗人类平衡障碍开辟了新的可能性，这些障碍在老年人群中的相关性越来越大。
Autophagy is an evolutionarily conserved process that is essential for cellular homeostasis and organismal viability in eukaryotes. However, the extent of its functions in higher-order processes of organismal physiology and behavior is still unknown. Here, we report that autophagy is essential for the maintenance of balance in mice and that its deficiency leads to severe balance disorders. We generated mice deficient in autophagin-1 protease (Atg4b) and showed that they had substantial systemic reduction of autophagic activity. Autophagy reduction occurred through defective proteolytic processing of the autophagosome component LC3 and its paralogs, which compromised the rate of autophagosome maturation. Despite their viability, Atg4b-null mice showed unusual patterns of behavior that are common features of inner ear pathologies. Consistent with this, Atg4b-null mice showed defects in the development of otoconia, organic calcium carbonate crystals essential for sense of balance (equilibrioception). Furthermore, these abnormalities were exacerbated in Atg5(-/-) mice, which completely lack the ability to perform autophagy, confirming that autophagic activity is necessary for otoconial biogenesis. Autophagy deficiency also led to impaired secretion and assembly of otoconial core proteins, thus hampering otoconial development. Taken together, these results describe an essential role for autophagy in inner ear development and equilibrioception and open new possibilities for understanding and treating human balance disorders, which are of growing relevance among the elderly population.