scholarly journals A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58

2020 ◽  
Vol 29 (9) ◽  
pp. 1520-1536 ◽  
Author(s):  
Karina Lezirovitz ◽  
Gleiciele A Vieira-Silva ◽  
Ana C Batissoco ◽  
Débora Levy ◽  
Joao P Kitajima ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mrna Expression ◽  
Autosomal Dominant ◽  
Spiral Ganglion ◽  
Copy Number Variations ◽  
Protein Coding ◽  
Ganglion Neurons ◽  
Genomic Duplication ◽  
Novel Protein

Abstract Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.

scholarly journals Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons

2020 ◽  
Vol 14 ◽  
Author(s):  
Francis Rousset ◽  
Vivianne B. C. Kokje ◽  
Rebecca Sipione ◽  
Dominik Schmidbauer ◽  
German Nacher-Soler ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Progenitor Cells ◽  
Ganglion Cells ◽  
Spiral Ganglion ◽  
Specific Cell ◽  
Auditory Neurons ◽  
Self Renewal ◽  
Starting Point ◽  
Ganglion Neurons

Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro. However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing–thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.

scholarly journals Functional Roles of High-Affinity Glutamate Transporters in Cochlear Afferent Synaptic Transmission in the Mouse

2010 ◽  
Vol 103 (5) ◽  
pp. 2581-2586 ◽  
Author(s):  
Zhiqiang Chen ◽  
Sharon G. Kujawa ◽  
William F. Sewell
Keyword(s):  
Hearing Loss ◽  
Otoacoustic Emissions ◽  
Excitatory Amino Acid ◽  
Spiral Ganglion ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Acoustic Stimulation ◽  
Noise Induced Hearing Loss ◽  
Glutamate Transporter 1 ◽  
Ganglion Neurons

In the cochlea, afferent transmission between inner hair cells and auditory neurons is mediated by glutamate receptors. Glutamate transporters located near the synapse and in spiral ganglion neurons are thought to maintain low synaptic levels of glutamate. We analyzed three glutamate transporter blockers for their ability to alter the effects of glutamate, exogenously applied to the synapse via perfusion of the scala tympani of the mouse, and compared that action to their ability to alter the effects of intense acoustic stimulation. Threo-beta-benzyloxyaspartate (TBOA) is a broad-spectrum glutamate transporter antagonist, affecting all three transporters [glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT1), and excitatory amino acid carrier 1 (EAAC1)]. l-serine- O-sulfate (SOS) blocks both GLAST and EAAC1 without effect on GLT1. Dihydrokainate (DHK) is selective for GLT1. Infusion of glutamate (10 μM for 220 min), TBOA (200 μM for 220 min), or SOS (100 μM for 180 min) alone did not alter auditory neural thresholds. When infused together with glutamate, TBOA and SOS produced significant neural threshold shifts, leaving otoacoustic emissions intact. In addition, both TBOA and SOS exacerbated noise-induced hearing loss by producing larger neural threshold shifts and delaying recovery. DHK did not alter glutamate- or noise-induced hearing loss. The evidence points to a major role for GLAST, both in protecting the synapse from exposure to excess extracellular glutamate and in attenuating hearing loss due to acoustic overstimulation.

scholarly journals Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Dalian Ding ◽  
Haiyan Jiang ◽  
Senthilvelan Manohar ◽  
Xiaopeng Liu ◽  
Li Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
High Frequency ◽  
Spiral Ganglion ◽  
Low Frequency ◽  
Nerve Fibers ◽  
Spiral Ganglion Neurons ◽  
Auditory Nerve Fibers ◽  
Ganglion Neurons

2-Hyroxypropyl-beta-cyclodextrin (HPβCD) is being used to treat Niemann-Pick C1, a fatal neurodegenerative disease caused by abnormal cholesterol metabolism. HPβCD slows disease progression, but unfortunately causes severe, rapid onset hearing loss by destroying the outer hair cells (OHC). HPβCD-induced damage is believed to be related to the expression of prestin in OHCs. Because prestin is postnatally upregulated from the cochlear base toward the apex, we hypothesized that HPβCD ototoxicity would spread from the high-frequency base toward the low-frequency apex of the cochlea. Consistent with this hypothesis, cochlear hearing impairments and OHC loss rapidly spread from the high-frequency base toward the low-frequency apex of the cochlea when HPβCD administration shifted from postnatal day 3 (P3) to P28. HPβCD-induced histopathologies were initially confined to the OHCs, but between 4- and 6-weeks post-treatment, there was an unexpected, rapid and massive expansion of the lesion to include most inner hair cells (IHC), pillar cells (PC), peripheral auditory nerve fibers, and spiral ganglion neurons at location where OHCs were missing. The magnitude and spatial extent of HPβCD-induced OHC death was tightly correlated with the postnatal day when HPβCD was administered which coincided with the spatiotemporal upregulation of prestin in OHCs. A second, massive wave of degeneration involving IHCs, PC, auditory nerve fibers and spiral ganglion neurons abruptly emerged 4–6 weeks post-HPβCD treatment. This secondary wave of degeneration combined with the initial OHC loss results in a profound, irreversible hearing loss.

scholarly journals Caffeine Induces Autophagy and Apoptosis in Auditory Hair Cells via the SGK1/HIF-1α Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Tang ◽  
Yuxuan Sun ◽  
Chenyu Xu ◽  
Xiaotao Guo ◽  
Jiaqiang Sun ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Spiral Ganglion Neurons ◽  
Auditory Hair Cells ◽  
Qrt Pcr ◽  
Ganglion Neurons

Caffeine is being increasingly used in daily life, such as in drinks, cosmetics, and medicine. Caffeine is known as a mild stimulant of the central nervous system, which is also closely related to neurologic disease. However, it is unknown whether caffeine causes hearing loss, and there is great interest in determining the effect of caffeine in cochlear hair cells. First, we explored the difference in auditory brainstem response (ABR), organ of Corti, stria vascularis, and spiral ganglion neurons between the control and caffeine-treated groups of C57BL/6 mice. RNA sequencing was conducted to profile mRNA expression differences in the cochlea of control and caffeine-treated mice. A CCK-8 assay was used to evaluate the approximate concentration of caffeine. Flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting were performed to detect the effects of SGK1 in HEI-OC1 cells and basilar membranes. In vivo research showed that 120 mg/ kg caffeine injection caused hearing loss by damaging the organ of Corti, stria vascularis, and spiral ganglion neurons. RNA-seq results suggested that SGK1 might play a vital role in ototoxicity. To confirm our observations in vitro, we used the HEI-OC1 cell line, a cochlear hair cell-like cell line, to investigate the role of caffeine in hearing loss. The results of flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting showed that caffeine caused autophagy and apoptosis via SGK1 pathway. We verified the interaction between SGK1 and HIF-1α by co-IP. To confirm the role of SGK1 and HIF-1α, GSK650394 was used as an inhibitor of SGK1 and CoCl2 was used as an inducer of HIF-1α. Western blot analysis suggested that GSK650394 and CoCl2 relieved the caffeine-induced apoptosis and autophagy. Together, these results indicated that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1α pathway, suggesting that caffeine may cause hearing loss. Additionally, our findings provided new insights into ototoxic drugs, demonstrating that SGK1 and its downstream pathways may be potential therapeutic targets for hearing research at the molecular level.

scholarly journals Autophagy Regulates the Survival of Hair Cells and Spiral Ganglion Neurons in Cases of Noise, Ototoxic Drug, and Age-Induced Sensorineural Hearing Loss

2021 ◽  
Vol 15 ◽  
Author(s):  
Lingna Guo ◽  
Wei Cao ◽  
Yuguang Niu ◽  
Shuangba He ◽  
Renjie Chai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Noise Exposure ◽  
Spiral Ganglion ◽  
Sensorineural Hearing ◽  
Spiral Ganglion Neurons ◽  
Core Components ◽  
Spontaneous Regeneration ◽  
Ganglion Neurons

Inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) are the core components of the auditory system. However, they are vulnerable to genetic defects, noise exposure, ototoxic drugs and aging, and loss or damage of HCs and SGNs results in permanent hearing loss due to their limited capacity for spontaneous regeneration in mammals. Many efforts have been made to combat hearing loss including cochlear implants, HC regeneration, gene therapy, and antioxidant drugs. Here we review the role of autophagy in sensorineural hearing loss and the potential targets related to autophagy for the treatment of hearing loss.

scholarly journals Gene therapy as a possible option to treat hereditary hearing loss

2020 ◽  
Vol 32 (2) ◽  
pp. 149-159
Author(s):  
Michael Morgan ◽  
Juliane W. Schott ◽  
Axel Rossi ◽  
Christian Landgraf ◽  
Athanasia Warnecke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Middle Ear ◽  
Hearing Aids ◽  
Spiral Ganglion ◽  
Primary Auditory Cortex ◽  
Auditory Pathway ◽  
Therapeutic Strategies ◽  
Sound Waves ◽  
Ganglion Neurons

Abstract The process of hearing involves a series of events. The energy of sound is captured by the outer ear and further transferred through the external auditory canal to the middle ear. In the middle ear, sound waves are converted into movements of the tympanic membrane and the ossicles, thereby amplifying the pressure so that it is sufficient to cause movement of the cochlear fluid. The traveling wave within the cochlea leads to depolarization of the inner ear hair cells that, in turn, release the neurotransmitter glutamate. Thereby, the spiral ganglion neurons are activated to transfer the signals via the auditory pathway to the primary auditory cortex. This complex combination of mechanosensory and physiological mechanisms involves many distinct types of cells, the function of which are impacted by numerous proteins, including those involved in ion channel activity, signal transduction and transcription. In the last 30 years, pathogenic variants in over 150 genes were found to be linked to hearing loss. Hearing loss affects over 460 million people world-wide, and current treatment approaches, such as hearing aids and cochlear implants, serve to improve hearing capacity but do not address the underlying genetic cause of hearing loss. Therefore, therapeutic strategies designed to correct the genetic defects causative for hearing loss offer the possibility to treat these patients. In this review, we will discuss genetic causes of hearing loss, novel gene therapeutic strategies to correct hearing loss due to gene defects and some of the preclinical studies in hearing loss animal models as well as the clinical translation of gene therapy approaches to treat hearing loss patients.

scholarly journals Mechanism and Prevention of Spiral Ganglion Neuron Degeneration in the Cochlea

2022 ◽  
Vol 15 ◽  
Author(s):  
Li Zhang ◽  
Sen Chen ◽  
Yu Sun
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Stem Cell ◽  
Cell Therapy ◽  
Sensory Neurons ◽  
Stem Cell Therapy ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neuron ◽  
Regeneration Ability ◽  
Ganglion Neurons

Sensorineural hearing loss (SNHL) is one of the most prevalent sensory deficits in humans, and approximately 360 million people worldwide are affected. The current treatment option for severe to profound hearing loss is cochlear implantation (CI), but its treatment efficacy is related to the survival of spiral ganglion neurons (SGNs). SGNs are the primary sensory neurons, transmitting complex acoustic information from hair cells to second-order sensory neurons in the cochlear nucleus. In mammals, SGNs have very limited regeneration ability, and SGN loss causes irreversible hearing loss. In most cases of SNHL, SGN damage is the dominant pathogenesis, and it could be caused by noise exposure, ototoxic drugs, hereditary defects, presbycusis, etc. Tremendous efforts have been made to identify novel treatments to prevent or reverse the damage to SGNs, including gene therapy and stem cell therapy. This review summarizes the major causes and the corresponding mechanisms of SGN loss and the current protection strategies, especially gene therapy and stem cell therapy, to promote the development of new therapeutic methods.

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