Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice

TY - JOUR

T1 - Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice

AU - Nolan, Lisa S.

AU - Chen, Jing

AU - Gonçalves, Ana Cláudia

AU - Bullen, Anwen

AU - Towers, Emily R.

AU - Steel, Karen P.

AU - Dawson, Sally J.

AU - Gale, Jonathan E.

N1 - Funding Information: We thank Lorenzo Preite for colony management. This work was supported by grants from the MRC [MR/N004329/1 to SD and JG; G0300212 to KPS] and the Wellcome Trust [091092/Z/09/Z to SD and JG; 100669, 098051 to KPS]. ACG was supported by an Action on Hearing Loss PhD Studentship [EI:595 to JG and SD]. Publisher Copyright: © 2022, The Author(s).

PY - 2022/2/14

Y1 - 2022/2/14

N2 - Cell cycle associated protein 1 (Caprin1) is an RNA-binding protein that can regulate the cellular post-transcriptional response to stress. It is a component of both stress granules and neuronal RNA granules and is implicated in neurodegenerative disease, synaptic plasticity and long-term memory formation. Our previous work suggested that Caprin1 also plays a role in the response of the cochlea to stress. Here, targeted inner ear-deletion of Caprin1 in mice leads to an early onset, progressive hearing loss. Auditory brainstem responses from Caprin1-deficient mice show reduced thresholds, with a significant reduction in wave-I amplitudes compared to wildtype. Whilst hair cell structure and numbers were normal, the inner hair cell-spiral ganglion neuron (IHC-SGN) synapse revealed abnormally large post-synaptic GluA2 receptor puncta, a defect consistent with the observed wave-I reduction. Unlike wildtype mice, mild-noise-induced hearing threshold shifts in Caprin1-deficient mice did not recover. Oxidative stress triggered TIA-1/HuR-positive stress granule formation in ex-vivo cochlear explants from Caprin1-deficient mice, showing that stress granules could still be induced. Taken together, these findings suggest that Caprin1 plays a key role in maintenance of auditory function, where it regulates the normal status of the IHC-SGN synapse.

AB - Cell cycle associated protein 1 (Caprin1) is an RNA-binding protein that can regulate the cellular post-transcriptional response to stress. It is a component of both stress granules and neuronal RNA granules and is implicated in neurodegenerative disease, synaptic plasticity and long-term memory formation. Our previous work suggested that Caprin1 also plays a role in the response of the cochlea to stress. Here, targeted inner ear-deletion of Caprin1 in mice leads to an early onset, progressive hearing loss. Auditory brainstem responses from Caprin1-deficient mice show reduced thresholds, with a significant reduction in wave-I amplitudes compared to wildtype. Whilst hair cell structure and numbers were normal, the inner hair cell-spiral ganglion neuron (IHC-SGN) synapse revealed abnormally large post-synaptic GluA2 receptor puncta, a defect consistent with the observed wave-I reduction. Unlike wildtype mice, mild-noise-induced hearing threshold shifts in Caprin1-deficient mice did not recover. Oxidative stress triggered TIA-1/HuR-positive stress granule formation in ex-vivo cochlear explants from Caprin1-deficient mice, showing that stress granules could still be induced. Taken together, these findings suggest that Caprin1 plays a key role in maintenance of auditory function, where it regulates the normal status of the IHC-SGN synapse.

UR - http://www.scopus.com/inward/record.url?scp=85124581254&partnerID=8YFLogxK

U2 - 10.1038/s41598-022-05657-2

DO - 10.1038/s41598-022-05657-2

M3 - Article

C2 - 35165318

AN - SCOPUS:85124581254

SN - 2045-2322

VL - 12

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 2444

ER -