Intracellular accumulation of mutant proteins causes proteinopathies, which lack targeted therapies. Autosomal dominant hearing loss (DFNA67) is caused by frameshift mutations in OSBPL2. Here, we show that DFNA67 is a toxic proteinopathy. Mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins. Consequently, its accumulation led to defective endolysosomal homeostasis and impaired autophagy. Transgenic mice expressing mutant OSBPL2 exhibited hearing loss, but osbpl2 knockout mice or transgenic mice expressing wild-type OSBPL2 did not. Rapamycin decreased the accumulation of mutant OSBPL2 and partially rescued hearing loss in mice. Rapamycin also partially improved hearing loss and tinnitus in individuals with DFNA67. Our findings indicate that dysfunctional autophagy is caused by mutant proteins in DFNA67; hence, we recommend rapamycin for DFNA67 treatment. Abbreviations: ABR: auditory brainstem response; ACTB: actin beta; CTSD: cathepsin D; dB: decibel; DFNA67: deafness non-syndromic autosomal dominant 67; DPOAE: distortion product otoacoustic emission; fs: frameshift; GFP: green fluorescent protein; HsQ53R-TG: human p.Q53Rfs*100-transgenic: HEK 293: human embryonic kidney 293; HFD: high-fat diet; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSHL: non-syndromic hearing loss; OHC: outer hair cells; OSBPL2: oxysterol binding protein-like 2; SEM: scanning electron microscopy; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: transgenic; WES: whole-exome sequencing; YUHL: Yonsei University Hearing Loss; WT: wild-type.
Bibliographical noteFunding Information:
This study was supported by the Yonsei University College of Medicine (Team Science Award 6-2021-0003 to H.Y.G. and 6-2021-0002 to J.J.), by the National Research Foundation of Korea (NRF) (2021R1A2C2003549 and 2018R1A5A2025079 to H.Y.G., 2020R1A2C3005787 to J.Y.C., 2019R1A2C1084033 to J.J. and Korea Mouse Phenotyping Project 2020M3A9D5A01082439 to H.Y.G.), and by the Ministry of Health and Welfare (2017M3A9E8029714). We thank the participating families for their contributions. We also thank Yonsei Advanced Imaging Centre in cooperation with Carl Zeiss Microscopy and the National Biobank of Korea, Centers for Disease Control and Prevention, Republic of Korea (4845-301, 4851-302 and −307).
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology