Paralemmin-3 – an essential constituent of the submembrane cytoskeleton of auditory hair cells

• Applicant: Dr. Christian Vogl
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467854023

Hearing relies on the precise conversion of physical sound waves into neural code. This challenging task is performed by sensory inner hair cells (IHCs), which – upon sound-induced activation – presynaptically release neurotransmitter. This process triggers action potential firing in the auditory nerve and initiates the flow of information along the auditory pathway towards the higher centers of the brain. In the initial steps of sound encoding, IHCs cooperate with a distinct type of hair cells – so-called outer hair cells (OHCs) – which enable localized mechanical amplification at frequency-specific sites along the cochlear axis via activity-dependent changes in their cell shape. This phenomenon plays a critical role in determining overall cochlear sensitivity. While external factors such as noise trauma and selected chemicals or medications can acutely induce the degeneration and loss of hair cells and thus lead to hearing impairment of even deafness, there is also a large fraction of genetic defects that can affect hearing performance. Thus, the identification and in-depth characterization of a multitude of genes and proteins – both, in humans, but also animal models – have greatly advanced our understanding of how hearing works on the molecular level. We have now identified a potential new deafness gene: paralemmin-3 (Palm3). Mutant mice for Palm3 exhibit a progressive early-onset hearing loss. Our initial analyses indicate that Palm3 specifically localizes to the plasma membranes of cochlear hair cells and moreover, that its genetic deletion induces a collapse of hair cell length and subsequent cell death. This may suggest a loss of structural integrity, stiffness and molecular organization of the hair cell plasma membrane, which – in particular for electromotile OHCs, but also IHCs – is of great importance for flawless functionality. The goal of our research proposal is therefore to investigate the role of Palm3 in hair cell structure and function. Using a combinatorial approach of high-resolution microscopy (confocal/STED; lightsheet microscopy), single-cell electrophysiology, systemsphysiological measurements and biochemical interaction studies, we plan to (i) clarify the subcellular distribution and molecular function of Palm3, (ii) characterize the effects of Palm3 loss in detail, (iii) identify molecular interactors of Palm3 and (iv) assess the potential for gene therapeutic restoration of cochlear function in Palm3 mutant mice.Considering the dramatic effects of genetic loss of Palm3 in regards to hair cell shape, function and survival, we expect that our planned analyses will generate novel important insights to advance our understanding of the molecular processes facilitating sound transduction in the cochlea. Moreover, this work will shed light on the cell biological function of the largely enigmatic paralemmin family. Finally, we expect to establish Palm3 as a novel deafness gene candidate for hereditary hearing loss.

• DFG Programme: Research Grants
• International Connection: Austria
• Co-Investigator: Professor Dr. Manfred W. Kilimann