Recent research has highlighted the role of FKBP5, a protein involved in glucocorticoid receptor signaling, within the cochlea of mice, shedding light on its potential impact on hearing loss. The study, conducted by researchers at Okayama University, focused on FKBP5 knockout (Fkbp5−/−) mice, who exhibited notable hearing impairments compared to their wild-type counterparts, especially at low frequencies.
Approximately 60.9 per 100,000 individuals are affected by idiopathic sudden sensorineural hearing loss (ISSNHL) annually, according to statistics from Japan, emphasizing the urgency of this research. The work presents promising avenues for therapeutic intervention, particularly as it reveals significant interactions between the FKBP5 protein and the mitogen-activated protein kinase (MAPK) signaling pathway, which is implicated in the body's response to acoustic trauma.
The study examined the auditory brainstem response (ABR) of Fkbp5−/− mice, finding elevated hearing loss levels, particularly at the 8 kHz frequency. Before any exposure to loud noise, the Fkbp5−/− mice had click-evoked ABR thresholds at 41.7 ± 4.1 dB SPL, significantly worse than wild-type mice which measured 32.9 ± 3.9 dB SPL. After being exposed to high-decibel sound levels of 114 dB SPL for two hours, both genotypes showed hearing loss across frequencies, but the initial differences observed pre-exposure diminished post-exposure, highlighting the impact of acoustic overexposure (AO).
This study thoroughly investigated the gene expression alterations linked to FKBP5 through RNA sequencing of the organ of Corti tissues. Results showed significant dysregulation of MAPK signaling pathway genes before and after acoustic trauma, which could explain the observed phenotypes of hearing loss. For wild-type mice, fundamental pathways associated with immune responses, such as the tumor necrosis factor (TNF) signaling pathway, were activated following acoustic trauma, underscoring the inflammatory mechanisms at play.
The data indicated 1,426 differentially expressed genes (DEGs) within wild-type mice compared to their pre-exposure states, and 3,839 DEGs when comparing Fkbp5−/− mice prior to acoustic exposure to wild-type mice. Subsequent analysis revealed systemic dysregulation across multiple pathways, prominently affecting MAPK signaling, which plays pivotal roles in cellular responses to external stimuli, including stress.
When assessing gene expressions post-acoustic exposure, the TNF signaling pathway emerged as the most significantly modulated. Key molecules p38 and Jun from the MAPK pathway were also found to be significantly impacted, supporting the hypothesis of FKBP5's regulatory role within this network. Notably, initial conditions of the Fkbp5−/− mice indicated inherent dysregulation of the MAPK pathway, potentially intensifying their vulnerability to hearing loss post-exposure.
The experimental design involved housing mice under controlled conditions with free access to food and water, followed by exposure to sound stimuli aimed at simulating conditions of acoustic trauma. Hearing function was evaluated through ABR testing across multiple frequencies at varying intervals after exposure. Results confirmed the expected auditory deficits post-exposure, validating the methods and providing strong evidence for the study's conclusions.
Immunohistochemical data corroborated earlier findings indicating FKBP5 expression within cochlear hair cells (HCs) and supportive cells, lending clarity to its physiological role. Notably, the expression levels revealed FKBP5 might be equally present within outer and inner hair cells, emphasizing its potential involvement across different cochlear regions.
The findings contribute to the growing corpus of knowledge surrounding FKBP5's role beyond purely stress response pathways, linking it with auditory functions and potential therapeutic targets for mitigating hearing loss. Given how common acute sensorineural hearing loss occurs and the limited options available for treatment, these insights could be pivotal for developing new intervention strategies.
This research aligns with the broader objective of elucidation of the roles of molecular chaperones like FKBP5 within sensory biology, offering potential pathways for pharmacological developments aimed at treating auditory conditions. With persistent efforts to validate these insights, including future investigations focused on the molecular underpinnings of these responses and their clinical relevance, this work could pave the way for innovative clinical applications and improved outcomes for patients suffering from hearing impairments.