한빛사논문
- 조회770
Young Ik Koha,†, Kyung Seok Oha,†, Jung Ah Kima, Byunghwa Nohb, Hye Ji Choib, Sun Young Jooa, John Hoon Rima, Hye-Youn Kima, Dong Yun Kima, Seyoung Yua, Da Hye Kimb, Sang-Guk Leec, Jinsei Jungb,*, Jae Young Choib,*, and Heon Yung Geea,*
aDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; bDepartment of Otorhinolaryngology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; cDepartment of Laboratory Medicine, Yonsei University College of Medicine, Seoul Seoul 03722 Republic of Korea
†These authors contributed equally to this work.
*Corresponding author.
Abstract
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.
논문정보
- Research article
- 2022년 03월 (BRIC 등록일 2022-03-18)
- 국내 연구진
- 의약학 > 유전 및 유전체의학
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