Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent

Satoe Takahashi; Kazuaki Homma; Yingjie Zhou; Shinichi Nishimura; Chongwen Duan; Jessie Chen; Aisha Ahmad; Mary Ann Cheatham; Jing Zheng

doi:10.1038/srep21973

Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent

Sci Rep. 2016 Feb 23:6:21973. doi: 10.1038/srep21973.

Authors

Satoe Takahashi¹, Kazuaki Homma^{1

2}, Yingjie Zhou³, Shinichi Nishimura^{4

5}, Chongwen Duan¹, Jessie Chen¹, Aisha Ahmad³, Mary Ann Cheatham^{3

2}, Jing Zheng^{1

2}

Affiliations

¹ Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.
² Knowles Hearing Center, Northwestern University, Evanston, IL 60208, USA.
³ Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA.
⁴ Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.
⁵ Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

2-Hydroxypropyl-beta-cyclodextrin
Animals
Brain / drug effects
Brain / metabolism
Brain / pathology
Cell Death / drug effects
Chelating Agents / administration & dosage
Chelating Agents / adverse effects*
Cholesterol / metabolism
Disease Susceptibility
Gene Expression
Hair Cells, Auditory, Outer / drug effects*
Hair Cells, Auditory, Outer / metabolism
Hair Cells, Auditory, Outer / pathology
Hearing Loss, Sensorineural / chemically induced
Hearing Loss, Sensorineural / genetics*
Hearing Loss, Sensorineural / pathology
Humans
Mice
Mice, Knockout
Molecular Motor Proteins / deficiency
Molecular Motor Proteins / genetics*
Neuroprotective Agents / administration & dosage
Neuroprotective Agents / adverse effects*
Niemann-Pick Disease, Type C / drug therapy
Niemann-Pick Disease, Type C / genetics
Niemann-Pick Disease, Type C / metabolism
Niemann-Pick Disease, Type C / pathology
Time-Lapse Imaging
beta-Cyclodextrins / administration & dosage
beta-Cyclodextrins / adverse effects*

Substances

Chelating Agents
Molecular Motor Proteins
Neuroprotective Agents
Pres protein, mouse
beta-Cyclodextrins
2-Hydroxypropyl-beta-cyclodextrin
Cholesterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding