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.

Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.

Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retina degeneration, obesity, kidney failure and cognitive impairment. In spite of a progress made in general understanding of BBS aetiology, the molecular mechanism of cognitive impairment remains elusive. Here we report that loss of Bardet-Biedl syndrome proteins causes synaptic dysfunction in principal neurons providing possible explanation for cognitive impairment phenotype in BBS patients. Using synaptosomal proteomics and immunocytochemistry we demonstrate the presence of Bbs in postsynaptic density of hippocampal neurons. Loss of Bbs results in the significant reduction of dendritic spines in principal neurons of Bbs mice models. Furthermore, we demonstrate that spine deficiency correlates with events that destabilize spine architecture, such as, impaired spine membrane receptors signalling known to be involved in the maintenance of dendritic spines. Finally, we show that voluntary exercise rescues spine deficiency in the neurons. Based on our data, we propose a model in which Bbs proteins, similar to their function in primary cilia, regulate trafficking of signalling receptors into and out of the membrane of dendritic spines, thus providing the basis for synaptic plasticity.