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Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux

ABSTRACT: ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann–Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanisms remain unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506∗) in Atp6v1b2, Atp6v1b2Arg506*/Arg506*. To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in Atp6v1b2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment.

SUBMITTER: Qiu S

PROVIDER: S-EPMC8568048 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:After hearing loss retrograde degeneration of spiral ganglion neurons (SGNs) has been described. Studies modeling the effects of degeneration mostly omitted peripheral processes (dendrites). Recent experimental observations indicated that degenerating SGNs manifested also a reduced diameter of their dendrites. We simulated populations of 400 SGNs inside a high resolution cochlear model with a cochlear implant, based on μCT scans of a human temporal bone. Cochlear implant stimuli were delivered as biphasic pulses in a monopolar configuration. Three SGN situations were simulated, based on our previous measurements of human SGN dendrites: (A) SGNs with intact dendrites (before degeneration), (B) degenerating SGNs, dendrites with a smaller diameter but original length, (C) degenerating SGNs, dendrites omitted. SGN fibers were mapped to characteristic frequency, and place pitch was estimated from excitation profiles. Results from degenerating SGNs (B, C) were similar. Most action potentials were initiated in the somatic area for all cases (A, B, C), except for areas near stimulating electrodes in the apex with intact SGNs (A), where action potentials were initiated in the distal dendrite. In most cases, degenerating SGNs had lower thresholds than intact SGNs (A) (down to -2 dB). Excitation profiles showed increased ectopic activation, i.e., activation of unintended neuronal regions, as well as similar neuronal regions excited by different apical electrodes, for degenerating SGNs (B, C). The estimated pitch showed cases of pitch reversals in apical electrodes for intact SGNs (A), as well as mostly identical pitches evoked by the four most apical electrodes for degenerating SGNs (B, C). In conclusion, neuronal excitation profiles to electrical stimulation exhibited similar traits in both ways of modeling SGN degeneration. Models showed degeneration of dendrites caused increased ectopic activation, as well as similar excitation profiles and pitch evoked by different apical electrodes. Therefore, insertion of electrodes beyond approximately 450° may not provide any benefit if SGN dendrites are degenerated.

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Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux

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