Deletion of Clusterin Protects Cochlear Hair Cells against Hair Cell Aging and Ototoxicity

Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.

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Noise-induced and age-related hearing loss: new perspectives and potential therapies

F1000Research ◽

10.12688/f1000research.11310.1 ◽

2017 ◽

Vol 6 ◽

pp. 927 ◽

Cited By ~ 78

Author(s):

M Charles Liberman

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Hair Cells ◽

Auditory Nerve ◽

Cell Loss ◽

Sensorineural Hearing ◽

Hair Cell Loss ◽

Age Related ◽

Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

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Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

International Journal of Molecular Sciences ◽

10.3390/ijms22158111 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8111

Author(s):

Kuang-Hsu Lien ◽

Chao-Hui Yang

Keyword(s):

Hearing Loss ◽

Sex Differences ◽

Sexual Dimorphism ◽

Sensorineural Hearing Loss ◽

Hormone Replacement ◽

Modern Society ◽

Sensorineural Hearing ◽

Drug Induced ◽

Age Related ◽

Age Related Hearing Loss

The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.

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Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.628712 ◽

2021 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Melanie Holmgren ◽

Lavinia Sheets

Keyword(s):

Cell Death ◽

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Lateral Line ◽

Hair Cells ◽

High Energy ◽

Sensorineural Hearing ◽

Mitochondrial Activity ◽

Ototoxic Drugs

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.

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Enhancing the sensitivity of the envelope-following response for cochlear synaptopathy screening in humans: the role of stimulus envelope

10.1101/2020.06.05.136184 ◽

2020 ◽

Cited By ~ 2

Author(s):

Viacheslav Vasilkov ◽

Markus Garrett ◽

Manfred Mauermann ◽

Sarah Verhulst

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Auditory Nerve ◽

Outer Hair Cell ◽

Cell Damage ◽

Modulation Depth ◽

Auditory Evoked Potential ◽

Sensorineural Hearing ◽

Age Related

AbstractAuditory de-afferentation, a permanent reduction in the number of innerhair-cells and auditory-nerve synapses due to cochlear damage or synaptopathy, can reliably be quantified using temporal bone histology and immunostaining. However, there is an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or lack of measurement sensitivity. To render AEP-based markers of synaptopathy more sensitive and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve physiology, we optimized the stimulus envelope to stimulate the available auditory-nerve population optimally and synchronously to generate strong envelope-following-responses (EFRs). We further used model simulations to explore which stimuli evoked a response that was sensitive to synaptopathy, while being maximally insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who had normal or impaired audiograms with suspected age-related synaptopathy in the older cohort. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120-Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recordings, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25% duty cycle and a 95% modulation depth. Older listeners with normal or impaired audiometric thresholds showed significantly reduced EFRs, which were consistent with how (age-induced) synaptopathy affected these responses in the model.Significance StatementCochlear synaptopathy was in 2009 identified as a new form of sensorineural hearing loss (SNHL) that also affects primates and humans. However, clinical practice does not routinely screen for synaptopathy, and hence its consequences for degraded sound and speech perception remain unclear. Cochlear synaptopathy may thus remain undiagnosed and untreated in the aging population who often report self-reported hearing difficulties. To enable an EEG-based differential diagnosis of synaptopathy in humans, it is crucial to develop a recording method that evokes a robust response and emphasizes inter-individual differences. These differences should reflect the synaptopathy aspect of SNHL, while being insensitive to other aspects of SNHL (e.g. outer-hair-cell damage). This study uniquely combines computational modeling with experiments in normal and hearing-impaired listeners to design an EFR stimulation and recording paradigm that can be used for the diagnosis of synaptopathy in humans.

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Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-106892 ◽

2020 ◽

pp. jmedgenet-2020-106892

Author(s):

Xue Gao ◽

Sha-Sha Huang ◽

Shi-Wei Qiu ◽

Yu Su ◽

Wei-Qian Wang ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Hair Cells ◽

Noonan Syndrome ◽

Sensorineural Hearing ◽

Supporting Cells ◽

Pathogenic Variants ◽

Underlying Mechanisms ◽

Ganglion Neurons ◽

Multiple Lentigines

BackgroundGermline variants in PTPN11 are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which share common skin and facial symptoms, cardiac anomalies and retardation of growth. Hearing loss is considered an infrequent feature in patients with NSML/NS. However, in our cohort, we identified a group of patients with PTPN11 pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence of PTPN11-related NSML or NS in patients with congenital SNHL and explored the expression of PTPN11 and the underlying mechanisms in the auditory system.MethodsA total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients with PTPN11 variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish with Ptpn11 knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes.ResultsTen NSML/NS probands were diagnosed via the identification of pathogenic variants of PTPN11, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded by Ptpn11, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown of ptpn11a and overexpression of mutant PTPN11 were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom in PTPN11-associated NSML or NS. Other features may be mild, especially in children.ConclusionScreening for PTPN11 in patients with congenital hearing loss and variant-based diagnoses are recommended.

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Research Progress on Flat Epithelium of the Inner Ear

Physiological Research ◽

10.33549/physiolres.934447 ◽

2020 ◽

pp. 775-785

Author(s):

L HE ◽

J-Y GUO ◽

K LIU ◽

G-P WANG ◽

S-S GONG

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Inner Ear ◽

Hair Cells ◽

Noise Exposure ◽

Sensory Epithelium ◽

Sensorineural Hearing ◽

Research Progress ◽

Supporting Cells ◽

Mesenchymal Transition

Sensorineural hearing loss and vertigo, resulting from lesions in the sensory epithelium of the inner ear, have a high incidence worldwide. The sensory epithelium of the inner ear may exhibit extreme degeneration and is transformed to flat epithelium (FE) in humans and mice with profound sensorineural hearing loss and/or vertigo. Various factors, including ototoxic drugs, noise exposure, aging, and genetic defects, can induce FE. Both hair cells and supporting cells are severely damaged in FE, and the normal cytoarchitecture of the sensory epithelium is replaced by a monolayer of very thin, flat cells of irregular contour. The pathophysiologic mechanism of FE is unclear but involves robust cell division. The cellular origin of flat cells in FE is heterogeneous; they may be transformed from supporting cells that have lost some features of supporting cells (dedifferentiation) or may have migrated from the flanking region. The epithelial-mesenchymal transition may play an important role in this process. The treatment of FE is challenging given the severe degeneration and loss of both hair cells and supporting cells. Cochlear implant or vestibular prosthesis implantation, gene therapy, and stem cell therapy show promise for the treatment of FE, although many challenges remain to be overcome.

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Research Progress on the Mechanism of Cochlear Hair Cell Regeneration

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.732507 ◽

2021 ◽

Vol 15 ◽

Author(s):

Shan Xu ◽

Ning Yang

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Hair Cells ◽

Molecular Mechanisms ◽

Sensorineural Hearing ◽

Research Progress ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Auditory Hair Cells

Mammalian inner ear hair cells do not have the ability to spontaneously regenerate, so their irreversible damage is the main cause of sensorineural hearing loss. The damage and loss of hair cells are mainly caused by factors such as aging, infection, genetic factors, hypoxia, autoimmune diseases, ototoxic drugs, or noise exposure. In recent years, research on the regeneration and functional recovery of mammalian auditory hair cells has attracted more and more attention in the field of auditory research. How to regenerate and protect hair cells or auditory neurons through biological methods and rebuild auditory circuits and functions are key scientific issues that need to be resolved in this field. This review mainly summarizes and discusses the recent research progress in gene therapy and molecular mechanisms related to hair cell regeneration in the field of sensorineural hearing loss.

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Codeficiency of Lysosomal Mucolipins 3 and 1 in Cochlear Hair Cells Diminishes Outer Hair Cell Longevity and Accelerates Age-Related Hearing Loss

Journal of Neuroscience ◽

10.1523/jneurosci.3368-17.2018 ◽

2018 ◽

Vol 38 (13) ◽

pp. 3177-3189 ◽

Cited By ~ 2

Author(s):

Teerawat Wiwatpanit ◽

Natalie N. Remis ◽

Aisha Ahmad ◽

Yingjie Zhou ◽

John C. Clancy ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Hair Cells ◽

Outer Hair Cell ◽

Cochlear Hair Cells ◽

Age Related ◽

Age Related Hearing Loss ◽

Cell Longevity

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Hearing loss caused by progressive degeneration of cochlear hair cells in mice deficient for the Barhl1 homeobox gene

Development ◽

10.1242/dev.129.14.3523 ◽

2002 ◽

Vol 129 (14) ◽

pp. 3523-3532 ◽

Cited By ~ 1

Author(s):

Shengguo Li ◽

Sandy M. Price ◽

Hugh Cahill ◽

David K. Ryugo ◽

Michael M. Shen ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Inner Ear ◽

Hair Cells ◽

Organ Of Corti ◽

Cochlear Hair Cells ◽

Sensory Hair ◽

Progressive Degeneration ◽

Age Related ◽

Sensory Hair Cells

The cochlea of the mammalian inner ear contains three rows of outer hair cells and a single row of inner hair cells. These hair cell receptors reside in the organ of Corti and function to transduce mechanical stimuli into electrical signals that mediate hearing. To date, the molecular mechanisms underlying the maintenance of these delicate sensory hair cells are unknown. We report that targeted disruption of Barhl1, a mouse homolog of the Drosophila BarH homeobox genes, results in severe to profound hearing loss, providing a unique model for the study of age-related human deafness disorders. Barhl1 is expressed in all sensory hair cells during inner ear development, 2 days after the onset of hair cell generation. Loss of Barhl1 function in mice results in age-related progressive degeneration of both outer and inner hair cells in the organ of Corti, following two reciprocal longitudinal gradients. Our data together indicate an essential role for Barhl1 in the long-term maintenance of cochlear hair cells, but not in the determination or differentiation of these cells.

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A study of cisplatin chemotherapy and hearing loss

International Journal of Otorhinolaryngology and Head and Neck Surgery ◽

10.18203/issn.2454-5929.ijohns20183705 ◽

2018 ◽

Vol 4 (5) ◽

pp. 1297 ◽

Cited By ~ 1

Author(s):

L. Sivasankari ◽

Lalitha Subramanian

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Hair Cells ◽

High Frequency ◽

Chemotherapeutic Agents ◽

Sensorineural Hearing ◽

Cochlear Hair Cells ◽

High Frequency Hearing Loss ◽

Auditory Monitoring

Background: Various medications have been associated with ototoxicity. Platinum containing chemotherapeutic agents are associated with cochleotoxicity, characterized by high frequency hearing loss. Cisplatin and related agents are absorbed by the cochlear hair cells, resulting in ototoxicity through the production of reactive oxygen species.Methods: About 67 patients, irrespective of the type of cancer, fit to undergo chemotherapy were considered for study after meticulous examination. Audiograms were taken prior to chemotherapy, at the end of each cycle of chemotherapy, and follow-up audiograms at 3 months and 6 months after completion of chemotherapy. Results: Among 37% of the patients with normal hearing, 10% of the patients developed sensorineural hearing loss after treatment. Among 63% of the patients with prior mild sensorineural hearing loss, 11.8% developed worsening of hearing after completion of treatment.Conclusions: Audiologic monitoring is important in patients undergoing cisplatin chemotherapy and post- chemotherapy auditory monitoring is essential to rehabilitate the patients with Sensorineural hearing loss.

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