In Silico Localization of Perilymph Proteins Enriched in Meńier̀e Disease Using Mammalian Cochlear Single-cell Transcriptomics

Alexandra M Arambula; Shoujun Gu; Athanasia Warnecke; Heike A Schmitt; Hinrich Staecker; Michael Hoa

doi:10.1097/ONO.0000000000000027

In Silico Localization of Perilymph Proteins Enriched in Meńier̀e Disease Using Mammalian Cochlear Single-cell Transcriptomics

Otol Neurotol Open. 2023 Mar 9;3(1):e027. doi: 10.1097/ONO.0000000000000027. eCollection 2023 Mar.

Authors

Alexandra M Arambula¹, Shoujun Gu², Athanasia Warnecke³, Heike A Schmitt³, Hinrich Staecker¹, Michael Hoa^{2

4}

Affiliations

¹ Department of Otolaryngology-Head & Neck Surgery, University of Kansas Medical Center, Kansas City, KS.
² Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, Bethesda, MD.
³ Department of Otolaryngology and Cluster of Excellence of the German Research Foundation (DFG; "Deutsche Forschungsgemeinschaft") "Hearing4all," Hannover Medical School, Hannover, Germany.
⁴ Department of Otolaryngology-Head and Neck Surgery, Georgetown University Medical Center, Washington, DC.

Abstract

Hypothesis: Proteins enriched in the perilymph proteome of Meńier̀e disease (MD) patients may identify affected cell types. Utilizing single-cell transcriptome datasets from the mammalian cochlea, we hypothesize that these enriched perilymph proteins can be localized to specific cochlear cell types.

Background: The limited understanding of human inner ear pathologies and their associated biomolecular variations hinder efforts to develop disease-specific diagnostics and therapeutics. Perilymph sampling and analysis is now enabling further characterization of the cochlear microenvironment. Recently, enriched inner ear protein expression has been demonstrated in patients with MD compared to patients with other inner ear diseases. Localizing expression of these proteins to cochlear cell types can further our knowledge of potential disease pathways and subsequent development of targeted therapeutics.

Methods: We compiled previously published data regarding differential perilymph proteome profiles amongst patients with MD, otosclerosis, enlarged vestibular aqueduct, sudden hearing loss, and hearing loss of undefined etiology (controls). Enriched proteins in MD were cross-referenced against published single-cell/single-nucleus RNA-sequencing datasets to localize gene expression to specific cochlear cell types.

Results: In silico analysis of single-cell transcriptomic datasets demonstrates enrichment of a unique group of perilymph proteins associated with MD in a variety of intracochlear cells, and some exogeneous hematologic and immune effector cells. This suggests that these cell types may play an important role in the pathology associated with late MD, suggesting potential future areas of investigation for MD pathophysiology and treatment.

Conclusions: Perilymph proteins enriched in MD are expressed by specific cochlear cell types based on in silico localization, potentially facilitating development of disease-specific diagnostic markers and therapeutics.

Keywords: Meńier̀e disease; Perilymph; Proteomics; RNA-Seq; Spiral ganglion neuron.