Gasparinho Gonçalves, AC; (2017) Understanding the role of stress granules in the inner ear. Doctoral thesis , UCL (University College London).

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Abstract

The human ear undergoes stress constantly. Exposure to noise, drugs or ageing contribute to the irreversible loss of hair cells, resulting in hearing loss. To understand why we go deaf, it is important to understand how the ear responds to stress. Stress granules (SGs) are aggregates of mRNA and proteins that are formed during stress. The SG-pathway has been implicated in the cochlea’s response to aminoglycoside antibiotics, suggesting that SGs play an important role during ototoxicity. Dysregulation of SG-formation has also been linked to neurodegeneration, supporting the hypothesis that SGs play a critical role in cell survival. Here, the formation and regulation of SGs have been investigated in an inner ear context using a combination of inner ear-derived UB/OC-2 cells, cochlear explants and the in-vivo mouse cochlea. Cells were labelled for two SG-proteins, TIA-1 and Caprin-1, and polyA+ mRNA was detected within SGs using RNA-immuno-FISH. A novel quantification method was developed to characterise in detail the number and size of SGs upon two stress paradigms, heat shock and arsenite. PolyA+ mRNA was observed to aggregate within SGs following different types of stress, suggesting that SGs are involved in post transcriptional regulation of gene expression in the cochlea. Experiments in cochlear explants suggest that pharmacological induction of SGs promotes outer hair cell survival during aminoglycoside exposure. In addition, SG formation was observed in the in-vivo C57BL/6 cochlea during ageing, suggesting that SGs may be related to cochlear degeneration. Hsp70, previously shown to promote hair cell survival following ototoxicity has been associated with SGs in other systems. Here, Hsp70 expression was evaluated in OC 2 cells following different stressors and evidence suggests it to be a key regulator of SGs. Taken together, these data implicate the SG pathway with maintenance of auditory function as a potential therapeutic target for further investigation.

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