Auditory and Otology Research

Auditory sensing in mammals occurs in a subdivision of the inner ear known as the cochlea. Sound pressure fluctuations are transmitted to the cochlea in several steps: vibrations of each eardrum, conduction through three small middle ear bones that act in a lever-like fashion, and production of pressure waves within the cochlea to displace the basilar membrane. Sound-induced basilar membrane motion excites the hair cells by deflecting their hair bundles to activate MET ion channels. Consequently, each hair cell produces responses that, near the threshold of hearing, are tuned to a characteristic frequency (CF).

Hearing loss is attributable to genetic factors, specific viral infections, chronic ear infections, birth complications, exposure to excessive noise, aging, and ototoxic drugs. Numerous proteins localized to sensory hair cells are critical for the normal development and maintenance of the intricate structure and function of the hair bundle; when defective, these are responsible for various forms of deafness. These include motor proteins, cytoskeletal proteins, adhesion proteins, and scaffolding proteins.

Fig.1 Structure and protein composition of the stereociliary bundle. (Robert, et al., 2006)

Membrane Protein in Auditory and Otology Research

• FAM65B

FAM65B is a plasma membrane-associated protein of hair cell stereocilia. The critical role of FAM65B in the human hearing was revealed by genetic analysis of a large family with hereditary deafness. In the zebrafish, knocking down the ortholog of FAM65B lead to sensorineural hearing loss.

• TMIE

TMIE (Transmembrane Inner Ear) is a transmembrane protein, localized in stereocilia at least in part near the lower tip-link insertion site and it has been linked to inherited forms of deafness.

• THMS

THMS (Tetraspan Membrane Protein of Hair Cell Stereocilia) is located on chromosome 6p21.3. According to the genetic and physical map positions of flanking markers. The protein TMHS encoding by THMS may play a role in deafness and balance dysfunction.

Fig.2 TMHS in Mechanosensory Hair Cell. (Wei, et al., 2012)

• TMC1

TMC1 encodes a protein required for the proper function and survival of inner ear hair cells. Recent evidence demonstrates that TMC1, and probably TMC2, are pore-forming components of mechanosensory transduction channels in auditory and vestibular hair cells. And mutations in Tmc1/TMC1 cause both dominant and recessive forms of deafness in mice and humans.

Fig.3 TMC1/2 in the auditory transduction. (Jia, et al., 2019)

• BAP31

BAP31, encoded by BCAP31, located in human Xq28 and highly expressed in neurons, is one of the most abundant ER membrane proteins. It is a chaperone protein involved in serval pathways. Studies have shown that loss-of-function mutations in BCAP31 are linked to dystonia, white-matter changes, and sensorineural deafness.

Fig.4 Function of BAP31 at Mitochondria-Associated Membranes. (Esben, 2021)

Treatments of Auditory and Otology Diseases

Genetic studies of families with hereditary hearing loss have led to the discovery of at least 40 genes associated with non-syndromic hearing loss, and more are being found each year. Such studies are proving to be a rich source of information about which molecules are important in the inner ear and give hope for new therapeutic approaches. These include strategies to prevent hair cell loss by gene manipulation through investigations of the use of stem cell technology as a treatment for cell loss.

References

1. Fettiplace, R.; et al. The sensory and motor roles of auditory hair cells. Nat Rev Neurosci. 2006, 7: 19-29.
2. Xiong, W.; et al. TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells. Cell. 2012, 151: 1283-1295.
3. Jia, Y.; et al. TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels. Neuron. 2020, 105: 310-321.e313.
4. Quistgaard, E.M. BAP31: Physiological functions and roles in disease. Biochimie. 2021, 186: 105-129.