title: Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent.
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.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.
authors.forename: Satoe
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.|Knowles Hearing Center, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Homma
authors.affiliation: Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.|Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.
authors.forename: Chongwen
authors.initials: C
authors.lastname: Duan
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA.|Knowles Hearing Center, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Cheatham
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.|Knowles Hearing Center, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002784:Cholesterol / Q000378:metabolism; D004198:Disease Susceptibility; D015870:Gene Expression; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020409:Molecular Motor Proteins / Q000172:deficiency / Q000235:genetics*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects*; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059008:Time-Lapse Imaging; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D002614:Chelating Agents; D020409:Molecular Motor Proteins; D018696:Neuroprotective Agents; C498720:Pres protein, mouse; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol