| Abstrakt: |
Healthy hearing is fundamentally dependent on the stereo-cilia bundles of cochlear hair cells. Recent studies on human post-mortem cochleas have shown that ageing is associated with structural impairment of these hair bundles, specifically in outer hair cells (OHCs) (Wu and Liberman, 2022). Genetic defects and environmental noise challenge the maintenance of the OHC hair bundle structure, contributing to age-related hearing loss. Several prior studies have described ste-reocilia fusion as a hair bundle pathology, yet often without a clear definition of this abnormality and its molecular mechanisms. Here, we aimed to elucidate the molecular anatomy of OHC stereocilia fusion by studying mouse models of ageing, prolonged noise-exposure, and cell-intrinsic stress caused by genetic perturbations. We utilised a novel imaging method to cochlear research, expansion microscopy, to generate super-resolution data of the OHC hair bundle structure and protein expression. Ageing in the C57BL/6J mice exhibited mild OHC stereocilia fusion, in most cases restricted to the lateral edges of hair bundles, indicating gradual progression of the fusion pathology. OHCs of young adult C57BL/6J mice exhibited elevated likelihood of stereocilia fusion following eight hours of daily, moderate-level noise-exposure (90 dB SPL) over the course of a week, with no evidence of recovery over one-month post-trauma period. Most severe phenotype was found in the genetic mouse model of perturbed endoplasmic reticulum homeostasis (ER stress), exhibiting adult-onset OHC stereocilia fusion with rapid progression to prominent fusion covering the whole hair bundle (Herranen et al., 2020; Ikakeimo et al., 2021). This severe pathology correlated with reduced FM1-43-dye uptake through the mechanotransduc-tion channels, loss of key stereociliary proteins (neuroplastin, PMCA2, myosin 7a, BAIAP2L2), and increased expression of the calcium buffer oncomodulin in the stereocilia, indicative of a major disturbance to mechanotransduction and to the Ca2+-balance required for stereocilia maintenance (Ikaheimo et al., 2024). These hair bundle abnormalities preceded OHC death, suggesting a window of opportunity to intervene with the maintenance of hair cell survival. We conclude that understanding the molecular anatomy of the hair bundle pathology might facilitate the development of targeted therapies for maintaining bundle integrity or to promote bundle repair. [ABSTRACT FROM AUTHOR] |
