Shin, J.-B. | Search bioRxiv

bioRxiv2018

LMO7 deficiency reveals the significance of the cuticular plate for hearing function

Sensory hair cells, the mechanoreceptors of the auditory and vestibular system, harbor two specialized organelles, the hair bundle and the cuticular plate. Both subcellular structures have adapted to facilitate the remarkable sensitivity and speed of hair cell mechanotransduction. While the mechanosensory hair bundle is extensively studied, the molecules and mechanisms mediating the development and function of the cuticular plate are poorly understood. The cuticular plate is believed to provide a rigid foundation for stereociliar pivot movements, but specifics about its function, especially the significance of its integrity for long-term maintenance of hair cell mechanotransduction, are not known. In this study, we describe the discovery of a hair cell protein called LIM only protein 7 (LMO7). In the hair cell, LMO7 is specifically localized in the cuticular plate. Lmo7 KO mice suffer multiple deficiencies in the cuticular plate, including reduced filamentous actin density and abnormal length and distribution of stereociliar rootlets. In addition to the cuticular plate defects, older Lmo7 KO mice develop abnormalities in inner hair cell stereocilia. Together, these defects affect cochlear tuning and sensitivity and give rise to late-onset progressive hearing loss.

neuroscience↗

bioRxiv2018

Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinases 1 and 3 (RIPK1 and 3). In this study, we used pharmacological and genetic intervention to test the relative contributions of necroptosis and caspase-8-mediated apoptosis towards cisplatin and aminoglycoside ototoxicity. We find that ex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while in vivo, both necroptosis and apoptosis are involved. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.\n\nSignificance statementThe clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.

neuroscience↗