Sodium-hydrogen exchanger 6 (NHE6) deficiency leads to hearing loss, via reduced endosomal signalling through the BDNF/Trk pathway.

Kucharava, Krystsina; Brand, Yves; Albano, Giuseppe; Sekulic-Jablanovic, Marijana; Glutz, Andrea; Xian, Xunde; Herz, Joachim; Bodmer, Daniel; Fuster, Daniel G.; Petkovic, Vesna (2020). Sodium-hydrogen exchanger 6 (NHE6) deficiency leads to hearing loss, via reduced endosomal signalling through the BDNF/Trk pathway. Scientific reports, 10(1), p. 3609. Springer Nature 10.1038/s41598-020-60262-5

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Acid-base homeostasis is critical for normal growth, development, and hearing function. The sodium-hydrogen exchanger 6 (NHE6), a protein mainly expressed in early and recycling endosomes, plays an important role in regulating organellar pH. Mutations in NHE6 cause complex, slowly progressive neurodegeneration. Little is known about NHE6 function in the mouse cochlea. Here, we found that all NHE isoforms were expressed in wild-type (WT) mouse cochlea. Nhe6 knockout (KO) mice showed significant hearing loss compared to WT littermates. Immunohistochemistry in WT mouse cochlea showed that Nhe6 was localized in the organ of Corti (OC), spiral ganglion (SG), stria vascularis (SV), and afferent nerve fibres. The middle and the inner ears of WT and Nhe6 KO mice were not different morphologically. Given the putative role of NHE6 in early endosomal function, we examined Rab GTPase expression in early and late endosomes. We found no change in Rab5, significantly lower Rab7, and higher Rab11 levels in the Nhe6 KO OC, compared to WT littermates. Because Rabs mediate TrkB endosomal signalling, we evaluated TrkB phosphorylation in the OCs of both strains. Nhe6 KO mice showed significant reductions in TrkB and Akt phosphorylation in the OC. In addition, we examined genes used as markers of SG type I (Slc17a7, Calb1, Pou4f1, Cal2) and type II neurons (Prph, Plk5, Cacna1g). We found that all marker gene expression levels were significantly elevated in the SG of Nhe6 KO mice, compared to WT littermates. Anti-neurofilament factor staining showed axon loss in the cochlear nerves of Nhe6 KO mice compared to WT mice. These findings indicated that BDNF/TrkB signalling was disrupted in the OC of Nhe6 KO mice, probably due to TrkB reduction, caused by over acidification in the absence of NHE6. Thus, our findings demonstrated that NHEs play important roles in normal hearing in the mammalian cochlea.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Faculty Institutions > NCCR TransCure

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Albano, Giuseppe, Fuster, Daniel Guido


600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology




Springer Nature




Daniel Guido Fuster

Date Deposited:

10 Mar 2020 14:55

Last Modified:

05 Dec 2022 15:37

Publisher DOI:


PubMed ID:





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