Valproic Acid Inhibits Progressive Hereditary Hearing Loss in a KCNQ4 Variant Model through HDAC1 Suppression.

Area of Science:

• Otolaryngology
• Genetics
• Pharmacology

Background:

• Genetic hearing loss, particularly from KCNQ4 variants, lacks effective treatments.
• KCNQ4 is crucial for cochlear hair cell function and ion homeostasis.
• The KCNQ4 p.W276S variant leads to significant hair cell loss due to impaired potassium recycling.

Purpose of the Study:

• To investigate the therapeutic potential of valproic acid (VPA) in a mouse model of KCNQ4-related hearing loss.
• To elucidate the molecular mechanisms underlying VPA's protective effects in the cochlea.

Main Methods:

• Systemic VPA administration in KCNQ4 p.W276S mutant mice.
• Assessment of hearing function and hair cell survival.
• Analysis of VPA's downstream effects, including gene activation (SMN) and histone acetylation (H4) in the cochlea.
• In vitro study using HEI-OC1 cells to examine KCNQ4-HSP90β interaction and HDAC1 inhibition.

Main Results:

• VPA treatment significantly attenuated hearing loss in the KCNQ4 p.W276S mouse model.
• VPA protected cochlear hair cells from cell death.
• VPA upregulated the survival motor neuron gene and increased histone H4 acetylation in the cochlea.
• In vitro, VPA enhanced KCNQ4 binding with HSP90β by inhibiting HDAC1.

Conclusions:

• Valproic acid demonstrates therapeutic efficacy in a mouse model of KCNQ4-associated progressive hearing loss.
• VPA's mechanism involves direct effects on the cochlea, including promoting hair cell survival and modulating gene expression.
• VPA is a promising candidate drug for treating late-onset progressive hereditary hearing loss caused by KCNQ4 variants.