OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin

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.

Automated summary

DFNA67 is a toxic proteinopathy caused by intracellular accumulation of mutant proteins, which leads to defective endolysosomal homeostasis and impaired autophagy. Treatment with rapamycin can decrease mutant protein accumulation and partially rescue hearing loss and tinnitus in mice and patients with DFNA67.