Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 21973 |
| Journal | Scientific reports |
| Volume | 6 |
| DOIs | |
| State | Published - Feb 23 2016 |
Funding
We thank Drs. Santos-Sacchi and Navaratnam for the stable HEK293T cell line. Imaging was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA06553 award to the Robert H Lurie Comprehensive Cancer Center. We also thank Dr. Arvanitis and Mr. Mui for assistance in imaging analyses. TIRF Imaging was performed on an Andor XDI Revolution microscope, purchased through the support of NCRR 1S10 RR031680-01. This work was supported by NIH grants DC011813 and RC1DC010633 to J.Z. and DC00089 to M.A.C. and a Hugh Knowles Leadership Fund Award to J.Z. by the Knowles Hearing Center.
ASJC Scopus subject areas
- General