Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1– deficient mice

Xudong Wu (1, 2) , Katherine A. Steigelman (1, 2) , Erik Bonten (3) , Huimin Hu (3) , Wenxuan He (4) , Tianying Ren (3) , Jian Zuo (1) , Alessandra d'Azzo (3)

1 Department of Developmental Neurobiology
2 Department of Anatomy and Neurobiology and Integrated Program in Biomedical Sciences
3 Department of Genetics and Tumor Cell Biology
4 Oregon Health & Sciences University

The neuraminidase-1 () knockout mouse model is a phenocopy of the lysosomal storage disease (LSD) sialidosis, characterized by multisystemic and neuropathic symptoms, including hearing loss. We have characterized the auditory defects in mice and found that hearing loss involves both conductive and sensorineural components. Auditory brainstem response (ABR) thresholds were significantly elevated in mice at P21 (48∼55 dB), and hearing loss appeared progressive (ABR threshold elevation 53∼66 dB at P60). At these ages mice accumulated cerumen in the external ear canal and had a thickened mucosa and inflammation in the middle ear. In cochleae of adult wild-type mice, Neu1 was expressed in several cell types in the stria vascularis, the organ of Corti, and spiral ganglion. Progressive morphological abnormalities such as extensive vacuolization were detected in the cochleae as early as P9. These early morphologic changes in cochleae were associated with oversialylation of several lysosomal associated membrane proteins (Lamps) in the stria vascularis. A marked increase in the expression and apical localization of Lamp-1 in marginal cells of the stria vascularis predicts exacerbation of lysosomal exocytosis into the endolymph. Consequently, the endolymphatic potential in mice was reduced by approximately 20 mV at ages P31–P44, which would cause dysfunction of transduction in sensory hair cells. This study suggests a molecular mechanism that contributes to hearing loss in sialidosis and identifies potential therapeutic targets.

Mots clés: Life Sciences

Xudong Wu, Katherine A. Steigelman, Erik Bonten, Huimin Hu, Wenxuan He, et al.. Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1– deficient mice. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2010, ⟨10.1016/j.bbadis.2009.10.008⟩. ⟨hal-00562944⟩