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 5

Prophylactic administration of TRC051384 accelerates recovery from noise exposure and prevents cochlear synaptopathy in male 16-week-old CBA/CaJ mice.

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Prophylactic administration of TRC051384 accelerates recovery from noise...
(A) ABR thresholds in vehicle-treated mice remained elevated at 3 days after noise (DAN) and did not fully recover at 32 kHz by 14 DAN. In contrast, TRC051384-treated mice recovered to baseline by 3 DAN at 8 and 16 kHz and by 14 DAN at all frequencies. (B–D) ABR Wave I amplitudes at 16, 24, and 32 kHz remained persistently reduced in vehicle-treated mice at high stimulus intensities through 14 DAN, whereas TRC051384-treated mice showed recovery by 3 DAN. (E) Representative cochlear whole-mount images from the 8, 16, and 32 kHz regions immunostained for CtBP2 (red) and GluA2 (green) in TRC051384- and vehicle-treated mice at 14 DAN. Scale bar, 10 μm. (F) Quantification of colocalized CtBP2/GluA2 puncta revealed significantly greater synaptic density in TRC051384-treated mice across most cochlear frequency regions, with the largest differences at higher frequencies. Mean synapses per IHC at 32 kHz were 15.09 ± 1.38 for TRC051384 and 8.26 ± 2.01 for vehicle; at 45 kHz, 14.67 ± 0.98 and 5.99 ± 1.23, respectively. (A–D) N = 17 TRC051384-treated and 7 vehicle-treated mice. (E and F) N = 14–17 TRC051384-treated and 6–7 vehicle-treated mice. (A–D) Adjusted P value * = < 0.05, ** = < 0.01, *** = < 0.001; (F) Data are represented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s post hoc correction.