Autophagy is essential for mouse sense of balance
Guillermo Mariño, … , José M.P. Freije, Carlos López-Otín
Guillermo Mariño, … , José M.P. Freije, Carlos López-Otín
Published June 23, 2010
Citation Information: J Clin Invest. 2010;120(7):2331-2344. https://doi.org/10.1172/JCI42601.
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Research Article

Autophagy is essential for mouse sense of balance

Abstract

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.

Authors

Guillermo Mariño, Alvaro F. Fernández, Sandra Cabrera, Yunxia W. Lundberg, Rubén Cabanillas, Francisco Rodríguez, Natalia Salvador-Montoliu, José A. Vega, Antonino Germanà, Antonio Fueyo, José M.P. Freije, Carlos López-Otín

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Figure 6

The correct localization of otoconial core proteins is dependent on autophagic activity.

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The correct localization of otoconial core proteins is dependent on auto...
(A) Representative immunofluorescence images of endogenous otolin, otopetrin, and Oc90 proteins in utricles from WT and Atg5–/– E15.5 embryos showing their mislocalization in the absence of autophagy. Both otolin and otopetrin presented a similar intracellular localization both in WT and Atg5–/– samples but were only detected in utricle lumen in autophagy-competent embryos (arrows). Oc90 (right) was mainly detected in WT samples inside utricle lumen, both at the developing otoconia (asterisk) and as a proteinaceous coral-like structure (arrows). In addition, Oc90 was also detected covering utricle epithelial and sensory cells in WT samples (arrowheads in top panels). In contrast, in Atg5–/– samples Oc90 was only detected inside non-sensory vestibular cells (arrowheads in bottom panels). (B) In P1 WT neonates, otolin and otopetrin were mainly detected in otoconial cores (arrows), whereas this localization was not observed in Atg5–/– samples. Similarly, in WT samples Oc90 was mainly detected in otoconial cores (right panel and arrow in left panel). In autophagy-impaired neonates, Oc90 localized both in utricle lumen, forming proteinaceous coral-like structures (right panel and arrows in left panel), and inside non-sensory cells (arrowheads). Scale bars: 50 μm (otolin, otopetrin, and left Oc90 panels); 30 μm (right Oc90 panels).