Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice.
Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice.
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DOI：
10.1016/j.bbadis.2009.10.008
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发表时间：
2010-02
影响因子：
6.2
通讯作者：
d'Azzo, Alessandra
中科院分区：
文献类型：
--
作者：
Wu, Xudong;Steigelman, Katherine A.;Bonten, Erik;Hu, Huimin;He, Wenxuan;Ren, Tianying;Zuo, Jian;d'Azzo, Alessandra
神经氨酸酶-1（Neu 1）基因敲除小鼠模型是溶酶体贮积病（LSD）唾液酸沉积症的表型，其特征为多系统和神经性症状，包括听力损失。我们已经描述了Neu 1 −/−小鼠的听觉缺陷，发现听力损失涉及传导和感觉神经成分。P21时Neu 1 −/−小鼠听性脑干反应（ABR）阈值显著升高（48~55 dB），听力损失呈进行性（P60时ABR阈值升高53~66 dB）。在这些年龄段，Neu 1 −/−小鼠的外耳道中积聚了耳垢，中耳粘膜增厚并发炎。在成年野生型小鼠耳蜗中，Neu 1在血管纹、Corti器官和螺旋神经节的几种细胞类型中表达。早在P9就在Neu 1 −/−耳蜗中检测到进行性形态异常，如广泛的空泡化。Neu 1 −/−耳蜗的这些早期形态学变化与血管纹中几种溶酶体相关膜蛋白（Lamps）的过度唾液酸化有关。血管纹边缘细胞中Lamp-1的表达和顶端定位的显著增加预示着溶酶体胞吐作用加剧进入内淋巴。因此，Neu 1 −/−小鼠的内淋巴电位在P31-P44年龄时降低了约20 mV，这将导致感觉毛细胞的转导功能障碍。这项研究提出了一种导致唾液酸中毒听力损失的分子机制，并确定了潜在的治疗靶点。
The neuraminidase-1 (Neu1) 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 Neu1−/− mice and found that hearing loss involves both conductive and sensorineural components. Auditory brainstem response (ABR) thresholds were significantly elevated in Neu1−/− mice at P21 (48~55 dB), and hearing loss appeared progressive (ABR threshold elevation 53~66 dB at P60). At these ages Neu1−/− 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 Neu1−/− cochleae as early as P9. These early morphologic changes in Neu1−/− 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 Neu1−/− 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.
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影响因子：
6.1
作者：
Kamphoven, JHJ;de Ruiter, MM;Reuser, AJJ
通讯作者：
Reuser, AJJ
影响因子：
4.8
作者：
Bonten, EJ;d'Azzo, A
通讯作者：
d'Azzo, A
DOI：
10.1016/s0165-5876(97)00176-6
发表时间：
1998-03-01
影响因子：
1.5
作者：
Komura, Y;Kaga, K;Suzuki, JI
通讯作者：
Suzuki, JI
DOI：
10.1016/j.ijporl.2006.09.016
发表时间：
2007-02-01
影响因子：
1.5
作者：
Schachern, Patricia A.;Cureoglu, Sebahattin;Whitley, Chester B.
通讯作者：
Whitley, Chester B.
DOI：
10.1152/ajprenal.00432.2006
发表时间：
2007-05-01
影响因子：
4.2
作者：
Nakaya, Kazuhiro;Harbidge, Donald G.;Marcus, Daniel C.
通讯作者：
Marcus, Daniel C.