Essential Role of Sptan1 in Cochlear Hair Cell Morphology and Function Via Focal Adhesion Signaling

Hearing loss is the most common human sensory deficit. Hearing relies on stereocilia, inserted into the cuticular plate of hair cells (HCs), where they play an important role in the perception of sound and its transmission. Although numerous genes have been associated with hearing loss, the function of many hair cell genes has yet to be elucidated. Herein, we focused on nonerythroid spectrin αII (SPTAN1), abundant in the cuticular plate, surrounding the rootlets of stereocilia and along the plasma membrane. Interestingly, mice with HC-specific Sptan1 knockout exhibited rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of HCs from middle and apical turns of the cochlea during early postnatal stages. Additionally, Sptan1 deficiency led to the decreased spreading of House Ear Institute-Organ of Corti 1 cells, and induced abnormal formation of focal adhesions and integrin signaling in mouse HCs. Altogether, our findings highlight SPTAN1 as a critical molecule for HC stereocilia morphology and auditory function via regulation of focal adhesion signaling.

Norrie disease protein is essential for cochlear hair cell maturation

Mutations in the gene for Norrie disease protein (Ndp) cause syndromic deafness and blindness. We show here that cochlear function in an Ndp knockout mouse deteriorated with age: At P3-P4, hair cells (HCs) showed progressive loss of Pou4f3 and Gfi1, key transcription factors for HC maturation, and Myo7a, a specialized myosin required for normal function of HC stereocilia. Loss of expression of these genes correlated to increasing HC loss and profound hearing loss by 2 mo. We show that overexpression of the Ndp gene in neonatal supporting cells or, remarkably, up-regulation of canonical Wnt signaling in HCs rescued HCs and cochlear function. We conclude that Ndp secreted from supporting cells orchestrates a transcriptional network for the maintenance and survival of HCs and that increasing the level of β-catenin, the intracellular effector of Wnt signaling, is sufficient to replace the functional requirement for Ndp in the cochlea.

Protective Effect of Ginsenoside Rd on Military Aviation Noise-Induced Cochlear Hair Cell Damage

Background Soldiers are often exposed to high-intensity noise produced by military weapons and equipment during activities, and the incidence of noise-induced hearing loss (NIHL) in many arms is high. Oxidative stress has a significant role in the pathogenesis of NIHL, and research has confirmed that ginsenoside Rd (GSRd) suppresses oxidative stress. Therefore, we hypothesized that GSRd may attenuate NIHL and cochlear hair cell loss, induced by military aviation noise stimulation, through the Sirtuin1/proliferator-activated receptor-gamma coactivator 1α (SIRT1/PGC-1α) signaling pathway.Methods Forty-eight male guinea pigs were randomly divided into four groups: control, noise stimulation, GSRd, and glycerol. The experimental groups received military helicopter noise stimulation at 115 dB (A) for 4 h daily for five consecutive days. Hair cell damage was evaluated by using inner ear basilar membrane preparation and scanning electron microscopy. Terminal dUTP nick end labeling and immunofluorescence staining were conducted. Changes in the SIRT1/PGC-1α signaling pathway and other apoptosis-related markers in the cochleae, as well as oxidative stress parameters were used as readouts.Results Loss of outer hair cells, more disordered cilia, prominent apoptosis, and elevated free radical levels were observed in the experimental groups. GSRd treatment markedly improved morphological changes and apoptosis through decreasing Bcl-2 associated X protein (Bax) expression and increasing Bcl-2 expression. In addition, GSRd upregulated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, decreased malondialdehyde (MDA) levels, and enhanced the activity of SIRT1 and PGC-1α messenger ribonucleic acid and protein expression.Conclusion GSRd can improve structural and functional damage to the cochleae caused by noise. The underlying mechanisms may be associated with the SIRT1/PGC-1α signaling pathway.

Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

Hearing loss is a common sensory deficit in both humans and dogs. In canines, the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in some mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6% and 0.04%, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate this LOXHD1-related hearing disorder from the population.

Up-regulation thioredoxin contributes to inhibite diabetic hearing impairment

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia. An association between DM and hearing impairment has been widely discussed. It’s essential to find effective prevetion or diagnosis of diabetic hearing loss. Thioredoxin (Trx) is a small molecule protein (12kDa) and plays biological functions such as anti-apoptotic, transcriptional regulation. In this study, our aim is to clarify the protective effect of Trx on diabetic hearing loss to find the early potential therapeutic target of diabetic hearing impairment in clinic in the future. Trx transgenic(Tg) mice was used to induce diabetic model by intraperitoneal injected Streptozotocin (STZ) and with/without SF or PX12 treatment. Succinate Dehydrogenase (SDH) Staining was used to evaluate the loss of hair cells. The relative expression of related proteins and genes was detected by Western blot and qRT-PCR. In diabetic mice, the outer hair cells were lost significantly. However, the loss of hair cells was delayed over-expression Trx. Moreover, the expression of PGC-1α, bcl-2 and LC3 was increased in Tg(+)-DM mice compared with Tg(-)-DM mice. The expression of ASK1, Txnip, GRP78, CHOP and p62 was decreased in Tg(+)-DM mice compared with Tg(-)-DM mice. Taken together, up-regulation Trx can protect cochlear hair cell from damage in diabetes. The underlying mechanism may be related to regulate ER stress through ASK1 and mitochondria pathway or autophagy via Txnip.