Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity

Abstract

Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases.

Otoprotective Effect of 2,3,4′,5-Tetrahydroxystilbene-2-O-β-d-Glucoside on Gentamicin-Induced Apoptosis in Mouse Cochlear UB/OC-2 Cells

“…There are few immortalized cell lines derived from the auditory sensory organ such as the House Ear Institute-Organ of Corti 1 (HEI-OC1), University of Bristol/Organ of Corti-1 (UB-OC-1) and UB/OC-2 cells. The cell line UB/OC-2, a conditionally immortalized mouse cochlear cell line derived from E13 embryos [32,33], has been used to study hereditary hearing loss [34], cell differentiation [35], ototoxicity [36] and otoprotection [31].…”

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

“…By these actions, SGs are described as triage centers for translation of mRNAs during stress exposure [ 17 ]. One leading hypothesis is that SGs are able to reshape translational patterns under stress exposure [ 19 , 51 ].…”

“…A growing tumor is an extremely dynamic environment where stressors, such as mechanical constriction, hypoxia and/or starvation (nutrient and/or glucose) play a role at multiple levels. SGs could play a critical role in integrating these stressors into changes in translation that leads to cancer progression [ 18 , 51 ]. Recent studies have demonstrated that such changes occur after exposure to hypoxia stress [ 18 , 54 , 55 , 56 ].…”

“…Of course, we cannot exclude that SGs proteins have additional and complementary roles to SGs in tumorigenesis. SGs have already been observed in vivo [ 26 , 51 , 164 ] and the presence of SG-like foci has been reported in in vivo mouse xenografted tumors [ 138 ]. Recently, the field is starting to observe SGs in clinical samples from patients with pancreatic adenocarcinoma [ 165 ].…”

The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration

“…The metabolic demands of sound detection and amplification elicits oxidative stress in neurons and hair cells that causes cell death unless tightly regulated 32,33 . We therefore tested the hypothesis that Chd7 mutant hair cells are hypersensitive to oxidative stress by exploiting a cochlear explant system in which oxidative stress can be induced by treatment with aminoglycosides 4,34,35 . When P6 control explants from Atoh1Cre/+;mTmG mice are exposed to gentamicin for 5 hours (100µM), hair cells are intact along the entire length of the cochlea, as are untreated Atoh1Cre/+;Chd7flox homozygous mutant hair cells (n=5/5 each; Figure 5).…”