Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling

Area of Science:

• Auditory neuroscience
• Cell biology
• Molecular signaling

Background:

• Traumatic noise exposure can lead to noise-induced hearing loss (NIHL) by affecting cochlear outer hair cells (OHCs).
• Rho-GTPase pathways are implicated in OHC death and NIHL, but the specific downstream effectors and mechanisms remain under investigation.

Purpose of the Study:

• To investigate the role of Rho-associated kinases (ROCKs) and ezrin-radixin-moesin (ERM) proteins in regulating the cochlear actin cytoskeleton following noise exposure.
• To elucidate the signaling cascade involving ROCK2 and ERM proteins in noise-induced hair cell loss and NIHL.

Main Methods:

• Utilized adult CBA/J mice subjected to noise-induced temporary threshold shift (TTS) and permanent threshold shift (PTS) hearing loss.
• Analyzed cochlear ROCK2 and phosphorylated ERM (p-ERM) levels, and the F/G-actin ratio.
• Administered lysophosphatidic acid (LPA) or used siRNA to modulate ROCK2 and radixin expression.

Main Results:

• Cochlear ROCK2 and p-ERM levels decreased after both TTS and PTS, but in OHCs, this decrease was specific to PTS.
• LPA treatment reversed noise-induced F/G-actin ratio changes, reduced OHC death, and attenuated NIHL.
• ROCK2 or radixin knockdown exacerbated NIHL, OHC loss, and the shift from TTS to PTS.

Conclusions:

• A ROCK2-mediated ERM-phosphorylation cascade is critical for modulating noise-induced hair cell loss and NIHL by regulating the actin cytoskeleton.
• Noise trauma diminishes RhoA and ROCK2, leading to ERM dephosphorylation and actin depolymerization, ultimately causing OHC damage.
• Targeting the ROCK2-ERM pathway, for instance with LPA, offers a potential therapeutic strategy for preventing NIHL.