Methionine sulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells

Abstract

Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically reduces methionine-R-sulfoxide to methionine. A recent genetic study showed that the MSRB3 gene is associated with autosomal recessive hearing loss in human deafness DFNB74. However, the precise role of MSRB3 in the auditory system and the pathogenesis of hearing loss have not yet been determined. This work is the first to generate MsrB3 knockout mice to elucidate the possible pathological mechanisms of hearing loss observed in DFNB74 patients. We found that homozygous MsrB3(-/-) mice were profoundly deaf and had largely unaffected vestibular function, whereas heterozygous MsrB3(+/-) mice exhibited normal hearing similar to that of wild-type mice. The MsrB3 protein is expressed in the sensory epithelia of the cochlear and vestibular tissues, beginning at E15.5 and E13.5, respectively. Interestingly, MsrB3 is densely localized at the base of stereocilia on the apical surface of auditory hair cells. MsrB3 deficiency led to progressive degeneration of stereociliary bundles starting at P8, followed by a loss of hair cells, resulting in profound deafness in MsrB3(-/-) mice. The hair cell loss appeared to be mediated by apoptotic cell death, which was measured using TUNEL and caspase 3 immunocytochemistry. Taken together, our data suggest that MsrB3 plays an essential role in maintaining the integrity of hair cells, possibly explaining the pathogenesis of DFNB74 deafness in humans caused by MSRB3 deficiency.

Methionine Sulfoxide Reductase A, B1 and B2 Are Likely to Be Involved in the Protection against Oxidative Stress in the Inner Ear

“…Therefore, even though one member of the Msr protein family is not expressed, other Msr proteins will compensate its function. In addition, we recently reported that MsrB3 was expressed especially in cochlear hair cells, and MsrB3 − / − mice showed profound hearing loss [Kwon et al, 2014]. However, MsrB3 − / − mice did not show abnormal vestibular behavior, such as circling or head tossing, despite wild-type expression of MsrB3 in the hair cells of the crista ampullaris, utricle and saccule in the vestibule [Kwon et al, 2014].…”

“…In addition, we recently reported that MsrB3 was expressed especially in cochlear hair cells, and MsrB3 − / − mice showed profound hearing loss [Kwon et al, 2014]. However, MsrB3 − / − mice did not show abnormal vestibular behavior, such as circling or head tossing, despite wild-type expression of MsrB3 in the hair cells of the crista ampullaris, utricle and saccule in the vestibule [Kwon et al, 2014]. In this study, we also found MsrB1 expression especially in the hair cells of the crista ampullaris, utricle and saccule in the vestibule.…”

“…In addition, we recently reported that MsrB3 protein is expressed in sensory epithelia in the cochlea and vestibular tissue of the mouse, and that loss of MsrB3 in mice led to profound hearing loss due to hair cell apoptosis [Kwon et al, 2014]. However, apart from MsrB3, the expression of Msr protein family members has not been reported in the inner ear.…”

Methionine Sulfoxide Reductase A Negatively Controls Microglia-Mediated Neuroinflammation via Inhibiting ROS/MAPKs/NF-κB Signaling Pathways Through a Catalytic Antioxidant Function

“…Detection of methionine sulfoxide was performed with the methionine sulfoxide immunoblotting kit (Cayman, Ann Arbor, MI) according to the manufacturer's protocol (28,45). The details are provided in the Supplementary Methods section.…”

Gene Expression Profiles of the Cochlea and Vestibular Endorgans

“…Methionine-R-sulfoxide reductase B3 (MSRB3) acts as an oxidoreductase, and its expression is only observed in hair, spiral ganglion, and inner phalangeal cell and Border and Deiters' cells. [65][66][67][68][69][70][71][72] Mutations in MSRB3 cause DFNB74, [65][66][67][68][69][70][71][72] revealing the importance of decreasing oxidative stress in the protection of hair and nerve cells. In contrast, many types of myosin and stereocillia components are not expressed in inner phalangeal, border, or Deiters' cells.…”