Loss of Pex1 in Inner Ear Hair Cells Contributes to Cochlear Synaptopathy and Hearing Loss

Area of Science:

• Genetics
• Neuroscience
• Otolaryngology

Background:

• Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic conditions linked to hearing impairment.
• Mutations in the PEX1 gene are a common cause of PBD-ZSD, but their specific impact on auditory function remains understudied.
• Sensory hair cells in the inner ear are susceptible to metabolic dysfunction, suggesting a potential link between peroxisomal defects and hearing loss.

Purpose of the Study:

• To investigate the role of PEX1 in the development and function of inner ear hair cells and auditory pathways.
• To explore the hypothesis that PEX1 mutations cause oxidative stress, leading to hair cell degeneration and hearing loss.

Main Methods:

• Created conditional knockout (cKO) mice by crossing floxed Pex1 mice with Gfi1 or VGlut3 expressing mice for targeted Pex1 deletion in inner ear hair cells.
• Assessed auditory function using auditory brainstem responses (ABR) and analyzed inner hair cell (IHC) synapses in cKO mice.
• Examined peroxisome number in IHCs to evaluate oxidative stress levels.

Main Results:

• Pex1 deletion in IHCs resulted in progressive hearing loss, evidenced by decreased ABR wave I amplitude, indicating synaptic dysfunction.
• Analysis revealed reduced ribbon synapse volume and altered exocytosis in IHCs of cKO mice.
• A decrease in peroxisome number was observed, suggesting an imbalance in oxidative stress.

Conclusions:

• PEX1 plays a crucial role in the development and maturation of inner hair cell-spiral ganglion synapses.
• PEX1 deficiency in hair cells leads to synaptic defects and subsequent hearing loss.
• These findings highlight the importance of PEX1 for maintaining auditory function and suggest oxidative stress as a contributing factor.