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J Neurosci. 2018 Feb 6. pii: 2487-17. doi: 10.1523/JNEUROSCI.2487-17.2018. [Epub ahead of print]

Noise-induced dysregulation of Quaking RNA binding proteins contributes to auditory nerve demyelination and hearing loss.

Author information

1
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
2
Department of Regenerative Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, United States langh@musc.edu barthj@musc.edu.
3
Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Departments of Oncology and Medicine, Montréal, Québec H3T 1E2, Canada.
4
Shanghai Jiao Tong University Affiliated Shanghai Sixth's People's Hospital, 600 Yishan Road, Shanghai, China.
5
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, United States langh@musc.edu barthj@musc.edu.

Abstract

Noise exposure causes auditory nerve (AN) degeneration and hearing deficiency, though the proximal biological consequences are not entirely understood. Most AN fibers and spiral ganglion neurons are ensheathed by myelinating glia that provide insulation and ensure rapid transmission of nerve impulses from the cochlea to the brain. Here we show that noise exposure administered to mice of either sex rapidly affects myelinating glial cells, causing molecular and cellular consequences that precede nerve degeneration. This response is characterized by demyelination, inflammation and widespread expression changes in myelin-related genes, including the RNA splicing regulator Quaking (QKI) and numerous QKI target genes. Analysis of mice deficient in QKI revealed that QKI production in cochlear glial cells is essential for proper myelination of spiral ganglion neurons and AN fibers, and for normal hearing. Our findings implicate QKI dysregulation as a critical early component in the noise response, influencing cochlear glia function that leads to AN demyelination and, ultimately, hearing deficiency.SIGNIFICANCE STATEMENTAuditory glia cells ensheath a majority of spiral ganglion neurons with myelin, protect auditory neurons and allow for fast conduction of electrical impulses along the auditory nerve. Here we show that noise exposure causes glial dysfunction leading to myelin abnormality and altered expression of numerous genes in the auditory nerve, including QKI, a gene implicated in regulating myelination. Study of a conditional mouse model that specifically depleted QKI in glia showed that QKI deficiency alone was sufficient to elicit myelin-related abnormality and auditory functional declines. These results establish QKI as a key molecular target in the noise response and a causative agent in hearing loss.

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