Document Type

Article

Publication Date

12-9-2022

Publication Title

Cells

Keywords

JMG, Animals, Mice, ATPases Associated with Diverse Cellular Activities, Cochlea, Deafness, Hair Cells, Auditory, Inner, Hearing, Hearing Loss, Mice, Knockout, Synapses

JAX Source

Cells. 2022;11(24).

Volume

11

Issue

24

ISSN

2073-4409

PMID

36552747

DOI

https://doi.org/10.3390/cells11243982

Grant

This work was partially supported by NIH grant to C. Lutz U42OD010921 Mutant Mouse Resource and Research Center and an award from the Global Foundation for Peroxisomal Disorders (GFPD) to G.S.G. Geleoc.

Abstract

Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin (PEX) genes have been found to cause PBD-ZSD with ~70% of patients harboring mutations in PEX1. Limited research has focused on the impact of peroxisomal disorders on auditory function. As sensory hair cells are particularly vulnerable to metabolic changes, we hypothesize that mutations in PEX1 lead to oxidative stress affecting hair cells of the inner ear, subsequently resulting in hair cell degeneration and hearing loss. Global deletion of the Pex1 gene is neonatal lethal in mice, impairing any postnatal studies. To overcome this limitation, we created conditional knockout mice (cKO) using Gfi1Cre or VGlut3Cre expressing mice crossed to floxed Pex1 mice to allow for selective deletion of Pex1 in the hair cells of the inner ear. We find that Pex1 excision in inner hair cells (IHCs) leads to progressive hearing loss associated with significant decrease in auditory brainstem responses (ABR), specifically ABR wave I amplitude, indicative of synaptic defects. Analysis of IHC synapses in cKO mice reveals a decrease in ribbon synapse volume and functional alterations in exocytosis. Concomitantly, we observe a decrease in peroxisomal number, indicative of oxidative stress imbalance. Taken together, these results suggest a critical function of Pex1 in development and maturation of IHC-spiral ganglion synapses and auditory function.

Comments

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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