Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent.
Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent.
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DOI：
10.1038/srep21973
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发表时间：
2016-02-23
影响因子：
4.6
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Takahashi S;Homma K;Zhou Y;Nishimura S;Duan C;Chen J;Ahmad A;Cheatham MA;Zheng J
C1型尼曼-匹克病（NPC 1）是一种由细胞内胆固醇运输受损引起的致命性遗传性疾病。最近的研究报告了2-羟丙基- β-环糊精（HPβCD）的耳毒性，HP β CD是胆固醇螯合剂，也是NPC唯一有希望的治疗方法1。由于外毛细胞（OHC）是唯一受HPβCD影响的耳蜗细胞，我们研究了普雷斯廷（一种OHC特异性运动蛋白）是否参与其中。单次高剂量HPβCD给药导致普雷斯廷野生型（WT）小鼠OHC死亡，而普雷斯廷敲除（KO）小鼠基底区OHC大部分幸免，暗示普雷斯廷参与HPβCD的耳毒性。我们发现普雷斯廷在体外可与胆固醇相互作用，提示HPβ CD诱导的耳毒性可能涉及这种相互作用的破坏。时间推移分析显示，从WT动物中分离的OHC在HPβCD治疗后迅速恶化，而prestin-KO中的OHC耐受相同的方案。提示HPβCD耳毒性可能与Prestin依赖性机制有关。
Niemann-Pick type C1 disease (NPC1) is a fatal genetic disorder caused by impaired intracellular cholesterol trafficking. Recent studies reported ototoxicity of 2-hydroxypropyl- β-cyclodextrin (HPβCD), a cholesterol chelator and the only promising treatment for NPC1. Because outer hair cells (OHCs) are the only cochlear cells affected by HPβCD, we investigated whether prestin, an OHC-specific motor protein, might be involved. Single, high-dose administration of HPβCD resulted in OHC death in prestin wildtype (WT) mice whereas OHCs were largely spared in prestin knockout (KO) mice in the basal region, implicating prestin’s involvement in ototoxicity of HPβCD. We found that prestin can interact with cholesterol in vitro, suggesting that HPβCD-induced ototoxicity may involve disruption of this interaction. Time-lapse analysis revealed that OHCs isolated from WT animals rapidly deteriorated upon HPβCD treatment while those from prestin-KOs tolerated the same regimen. These results suggest that a prestin-dependent mechanism contributes to HPβCD ototoxicity.