Progressive Hearing Loss in Mice Carrying a Mutation in Usp53

Area of Science:

• Genetics
• Neuroscience
• Otolaryngology

Background:

• Disordered protein ubiquitination is linked to neurodegenerative diseases.
• The role of ubiquitination in inner ear homeostasis and hearing loss is largely unknown.
• Auditory hair cells are vital for hearing and susceptible to degeneration.

Purpose of the Study:

• To investigate the genetic cause of progressive hearing loss in the mambo mouse line.
• To determine the function of the Usp53 gene in the inner ear.
• To explore the role of USP53 in maintaining hearing and inner ear homeostasis.

Main Methods:

• Forward genetics screen to identify mutation in mambo mice.
• Gene sequencing to identify mutation in Usp53.
• Immunofluorescence and co-localization studies to determine USP53 localization.
• Biotin tracer assay to assess tight junction barrier properties.
• Organotypic cochlear cultures to test hair cell survival.

Main Results:

• A mutation in Usp53 causes progressive hearing loss in mambo mice.
• USP53 is a catalytically inactive deubiquitinating enzyme expressed in cochlear hair cells.
• USP53 interacts with tight junction proteins TJP1 and TJP2.
• Outer hair cells degenerate postnatally in mambo mice.
• Reduced endocochlear potential observed in adult mambo mice.
• Hair cell loss is triggered by extracellular factors and rescued in low potassium milieu.
• Heterozygous mambo mice show increased susceptibility to noise-induced hearing loss.

Conclusions:

• USP53 is a novel tight junction-associated protein essential for auditory hair cell survival.
• USP53 plays a critical role in maintaining inner ear homeostasis and normal hearing.
• Dysfunction of USP53 may contribute to hereditary hearing loss in humans.