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Wfs1 敲入小鼠阐明了 Wfs1 在耳蜗内电位产生中的基本作用。

Wfs1 knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production.

机构信息

MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.

INM, Univ Montpellier, INSERM, Montpellier, France.

出版信息

Cell Death Dis. 2023 Jun 29;14(6):387. doi: 10.1038/s41419-023-05912-y.

DOI:10.1038/s41419-023-05912-y
PMID:37386014
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10310813/
Abstract

Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1 line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na/KATPase β1 subunit, a key protein for the maintenance of the EP. Overall, our data support a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na/KATPase β1 subunit.

摘要

沃尔夫拉明综合征（WS）是一种罕见的神经退行性疾病，包括糖尿病、尿崩症、视神经萎缩、听力损失（HL）以及神经紊乱。没有一种病理学的动物模型会出现早期 HL，这阻碍了对沃尔弗拉明（WFS1）蛋白在听觉通路中作用的理解，WFS1 蛋白负责 WS。我们生成了一种敲入小鼠，即 Wfs1 系，其携带导致受影响个体严重耳聋的人类突变。纯合子小鼠表现出明显的出生后 HL 和前庭综合征，内淋巴液（EP）崩溃，以及血管纹和感觉神经上皮的破坏性改变。突变蛋白阻止了 Na/KATPase β1 亚基这种 EP 维持的关键蛋白在细胞表面的定位。总的来说，我们的数据支持 WFS1 通过其结合伴侣 Na/KATPase β1 亚基，在 EP 和血管纹的维持中发挥关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/4aadac167eaf/41419_2023_5912_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/b69a40a7853a/41419_2023_5912_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/44f898d928a6/41419_2023_5912_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/c716e6aa3013/41419_2023_5912_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/c7a2312adf6c/41419_2023_5912_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/8168986d3410/41419_2023_5912_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/4aadac167eaf/41419_2023_5912_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/b69a40a7853a/41419_2023_5912_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/44f898d928a6/41419_2023_5912_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/c716e6aa3013/41419_2023_5912_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/c7a2312adf6c/41419_2023_5912_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/8168986d3410/41419_2023_5912_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/409d/10310813/4aadac167eaf/41419_2023_5912_Fig6_HTML.jpg

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