Heat shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss
Jintao Yu, Miguel A. Ramirez, Yi-Zhi Wang, Seby Edassery, Maxwell Shramuk, SangEun Yeom, Casey Jiaxi Li, Yuvraj Joshi, Mary Ann Cheatham, Mark A. Rutherford, Leah J. Welty, Jeffrey N. Savas
Jintao Yu, Miguel A. Ramirez, Yi-Zhi Wang, Seby Edassery, Maxwell Shramuk, SangEun Yeom, Casey Jiaxi Li, Yuvraj Joshi, Mary Ann Cheatham, Mark A. Rutherford, Leah J. Welty, Jeffrey N. Savas
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Research Article Aging Neuroscience Otology

Heat shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss

Abstract

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA-seq and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood-labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin-proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in SGNs as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.

Authors

Jintao Yu, Miguel A. Ramirez, Yi-Zhi Wang, Seby Edassery, Maxwell Shramuk, SangEun Yeom, Casey Jiaxi Li, Yuvraj Joshi, Mary Ann Cheatham, Mark A. Rutherford, Leah J. Welty, Jeffrey N. Savas

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Figure 1

Two-hour exposure to 100 dB SPL noise produces temporary threshold shift, persistent cochlear synaptopathy, and induction of ER chaperone genes in 16-week-old male CBA/CaJ mice.

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Two-hour exposure to 100 dB SPL noise produces temporary threshold shift...
(A) ABR thresholds recovered to baseline by 14 days after noise (DAN). (B) Representative 32 kHz ABR traces at 90 dB SPL before noise and 14 DAN. (C) Wave I amplitudes at 32 kHz remained significantly reduced at 14 DAN across 60–90 dB SPL; differences were estimated by linear mixed modeling. (D) Representative 32 kHz cochlear regions immunostained for CtBP2 (red) and GluA2 (green) from unexposed and noise-exposed mice at 14 DAN. Scale bar = 10 μm. (E) Quantification of overlapping CtBP2/GluA2 puncta revealed marked synapse loss from 20–45 kHz at 14 DAN (7.45 ± 2.53 synapses/IHC) versus unexposed controls (15.46 ± 0.89). (F) t-SNE of bulk cochlear RNA-seq profiles collected immediately, 4 h, or 8 h after noise and from unexposed controls showed clustering by exposure/recovery time. (G) Gene Ontology (GO) cellular component (CC) enrichment analysis identified endoplasmic reticulum chaperone complex (GO:0034663) as the most enriched term at 4 h. (H) Volcano plot depicting noise-induced changes in cochlear gene expression in the 4-hour postexposure group relative to unexposed controls. Significantly increased genes (P < 0.01) are red, with ER chaperone-complex genes highlighted. (I) Hsp90b1, Dnajb11, Dnajc13, Sdf2l1, and Hspa5 had elevated expression immediately following noise exposure and peaked at 4 hours postexposure. (J) Hsf1 and Hspa1a expression in cochlea. A priori contrasts comparing postnoise time points with controls yielded P = 0.026 and P = 0.43, respectively. Quantitative data are mean ± SD unless otherwise indicated. A–C, N = 6; D and E, N = 4 control/6 exposed; F–I, N = 4/group; J, N = 3/group.