Heat Shock Proteins in Human Perilymph: Implications for Cochlear Implantation

Schmitt, H.; Roemer, Ariane; Zeilinger, Carsten; Salcher, Rolf; Ďurišin, Martin; Staecker, Hinrich; Lenarz, Thomas; Warnecke, Athanasia

doi:10.1097/mao.0000000000001625

Cited by 26 publications

(21 citation statements)

References 41 publications

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“…The population of the patients included into our analysis is highly heterogenous with different anatomic and molecular pathologies. This can certainly add to the variability in the perilymph proteome that we showed in this study and in prior studies (Schmitt et al, 2017, 2018). In addition, different cochlear implant devices with various electrode arrays have been used for the treatment of the hearing loss, adding more variables to be considered when analyzing the hearing performance with the device.…”

Section: Discussionsupporting

confidence: 67%

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Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss

et al. 2019

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The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients ( n = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph ( n = 41) obtained from hearing-impaired patients ( n = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.

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Section: Discussionsupporting

confidence: 67%

“…Active exclusion was activated so that ions fragmented once were excluded from further fragmentation for 70 s within a mass window of 10 ppm of the specific m/z value. The relative protein quantification was performed by LFQ and was determined as LFQ intensity (Schmitt et al, 2017, 2018).…”

Section: Methodsmentioning

confidence: 99%

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss

et al. 2019

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“…The mechanisms are mostly unknown, therefore characterization of the perilymph proteome in VS patients may provide a valuable addition to understand the mechanisms of tumor-associated hearing loss. Recently studies of the proteome were applied to investigate various heat shock proteins, and they might be of importance for preservation of residual hearing after cochlear implantation [ 20 ]. However, we could not replicate this in our study since we only detected three variations of Heat shock 70KDa proteins in only a single patient.…”

Section: Discussionmentioning

confidence: 99%

The proteome of perilymph in patients with vestibular schwannoma. A possibility to identify biomarkers for tumor associated hearing loss?

et al. 2018

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BackgroundDue to the surrounding bone, the human inner ear is relatively inaccessible and difficult to reach for cellular and molecular analyses. However, these types of investigations are needed to better understand the etiology, pathophysiology and progression of several inner ear disorders. Moreover, the fluid from the inner ear cannot be sampled for micro-chemical analyses from healthy individuals in vivo. Therefore, in the present paper, we studied patients with vestibular schwannoma (VS) undergoing trans-labyrinthine surgery (TLS). Our primary aim was to identify perilymph proteins in patients with VS on an individual level. Our second aim was to investigate the proteins identified at a functional level and our final aim was to search for biological markers for tumor-associated hearing loss and tumor diameter.Methods and findingsSixteen patients underwent TLS for sporadic VS. Perilymph was aspirated through the round window before opening the labyrinth. One sample was contaminated and excluded resulting in 15 usable samples. Perilymph samples were analyzed with an online tandem LTQ-Orbitrap mass spectrometer. Data were analyzed with MaxQuant software to identify the total number of proteins and to quantify proteins in individual samples. Protein function was analyzed using the PANTHER Overrepresentation tool. Associations between perilymph protein content, clinical parameters, tumor-associated hearing loss and tumor diameter were assessed using Random Forest and Boruta. In total, 314 proteins were identified; 60 in all 15 patients and 130 proteins only once in 15 patients. Ninety-one proteins were detected in at least 12 out of 15 patients. Random Forest followed by Boruta analysis confirmed that alpha-2-HS-glycoprotein (P02765) was an independent variable for tumor-associated hearing loss. In addition, functional analysis showed that numerous processes were significantly increased in the perilymph. The top three enriched biological processes were: 1) secondary metabolic processes; 2) complement activation and 3) cell recognition.ConclusionsThe proteome of perilymph in patients with vestibular schwannoma has an inter-individual stable section. However, even in a cohort with homogenous disease, the variation between individuals represented the majority of the detected proteins. Alpha-2-HS-glycoprotein, P02765, was shown to be an independent variable for tumor-associated hearing loss, a finding that needs to be verified in other studies. In pathway analysis perilymph had highly enriched functions, particularly in terms of increased immune and metabolic processes.

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“…Due to the lack of biopsy sampling without the destruction of the organ, little is known about the cellular and molecular correlates in inner ear pathology (16).…”

Section: Biological Markersmentioning

confidence: 99%

“…Heat shock proteins (HSPs) are stress proteins, which mediate cell survival under critical environmental conditions (25). Increased perilymph levels of 10 different subgroups of HSP were detected in subjects undergoing cochlear implantation that preserved hearing when compared with those without hearing preservation, and cochlear transcriptome data suggest that there is a baseline protective expression of HSP70 1A, 1B, 2, 4, 5, 6, 8, 9, and 12A mRNA (16).…”

Section: Biological Markersmentioning

confidence: 99%

Biomarkers in Vestibular Schwannoma–Associated Hearing Loss

et al. 2019

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Vestibular schwannomas (VSs) are benign tumors composed of differentiated neoplastic Schwann cells. They can be classified into two groups: sporadic VS and those associated with neurofibromatosis type 2 (NF2). VSs usually grow slowly, initially causing unilateral sensorineural hearing loss (HL) and tinnitus. These tumors cause HL both due to compression of the auditory nerve or the labyrinthine artery and due to the secretion of different substances potentially toxic to the inner ear or the cochlear nerve. As more and more patients are diagnosed and need to be managed, we are more than ever in need of searching for biomarkers associated with these tumors. Owing to an unknown toxic substance generated by the tumor, HL in VS may be linked to a high protein amount of perilymph. Previous studies have identified perilymph proteins correlated with tumor-associated HL, including μ-Crystallin (CRYM), low density lipoprotein receptor-related protein 2 (LRP2), immunoglobulin (Ig) γ-4 chain C region, Ig κ-chain C region, complement C3, and immunoglobulin heavy constant γ 3. Besides, the presence of specific subtypes of heat shock protein 70 has been suggested to be associated with preservation of residual hearing. It has been recently demonstrated that chemokine receptor-4 (CXCR4) is overexpressed in sporadic VS as well as in NF2 tumors and that hearing disability and CXCR4 expression may be correlated. Further, the genetic profile of VS and its relationship with poor hearing has also been studied, including DNA methylation, deregulated genes, growth factors, and NF2 gene mutations. The knowledge of biomarkers associated with VS would be of significant value to maximize outcomes of hearing preservation in these patients.

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Heat Shock Proteins in Human Perilymph: Implications for Cochlear Implantation

Cited by 26 publications

References 41 publications

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss

The proteome of perilymph in patients with vestibular schwannoma. A possibility to identify biomarkers for tumor associated hearing loss?

Biomarkers in Vestibular Schwannoma–Associated Hearing Loss

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