Some individuals with noise-induced hearing loss (NIHL) also report balance problems. These accompanying vestibular complaints are not well understood. The present study used a rat model to examine the effects of noise exposure on the vestibular system. Rats were exposed to continuous broadband white noise (0–24kHz) at an intensity of 116dB sound pressure level (SPL) via insert ear phones in one ear for three hours under isoflurane anesthesia. Seven days after the exposure, a significant increase in ABR threshold (43.3±1.9dB) was observed in the noise-exposed ears, indicating hearing loss. Effects of noise exposure on vestibular function were assessed by three approaches. First, fluorescein-conjugated phalloidin staining was used to assess vestibular stereocilia following noise exposure. This analysis revealed substantial sensory stereocilia bundle loss in the saccular and utricular maculae as well as in the anterior and horizontal semicircular canal cristae, but not in the posterior semicircular canal cristae. Second, single unit recording of vestibular afferent activity was performed under pentobarbital anesthesia. A total of 548 afferents were recorded from 10 noise-treated rats and 12 control rats. Noise exposure produced a moderate reduction in baseline firing rates of regular otolith afferents and anterior semicircular canal afferents. Also a moderate change was noted in the gain and phase of the horizontal and anterior semicircular canal afferent’s response to sinusoidal head rotation (1 and 2Hz, 45 degrees/s peak velocity). Third, noise exposure did not result in significant changes in gain or phase of the horizontal rotational and translational vestibular-ocular reflex (VOR). These results suggest that noise exposure not only causes hearing loss, but also causes substantial damage in the peripheral vestibular system in the absence of immediate clinically measurable vestibular signs. These peripheral deficits, however, may lead to vestibular disorders over time.
Perturbation of huntingtin (HTT)’s physiological function is one postulated pathogenic factor in Huntington’s disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT’s conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT. Additionally, loss of HAP40 resulted in similar phenotypes as HTT knockout. More strikingly, HAP40 strongly affected HTT’s stability, as depletion of HAP40 significantly reduced the levels of endogenous HTT protein while HAP40 overexpression markedly extended its half-life. Conversely, in the absence of HTT, the majority of HAP40 protein were degraded, likely through the proteasome. Further, the affinity between HTT and HAP40 was not significantly affected by polyglutamine expansion in HTT, and contrary to an early report, there were no abnormal accumulations of endogenous HAP40 protein in HD cells from mouse HD models or human patients. Lastly, when tested in Drosophila models of HD, HAP40 partially modulated the neurodegeneration induced by full-length mutant HTT while showed no apparent effect on the toxicity of mutant HTT exon 1 fragment. Together, our study uncovers a conserved mechanism governing the stability and in vivo functions of HTT and demonstrates that HAP40 is a central and positive regulator of endogenous HTT. Further, our results support that mutant HTT is toxic regardless of the presence of its partner HAP40, and implicate HAP40 as a potential modulator of HD pathogenesis through its multiplex effect on HTT’s function, stability and the potency of mutant HTT’s toxicity.
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