Homeostatic maintenance and age-related functional decline in the Drosophila ear

Abstract

Age-related hearing loss (ARHL) is a threat to future human wellbeing. Multiple factors contributing to the terminal auditory decline have been identified; but a unified understanding of ARHL-or the homeostatic maintenance of hearing before its breakdown-is missing. We here present an in-depth analysis of homeostasis and ageing in the antennal ears of the fruit fly Drosophila melanogaster. We show that Drosophila, just like humans, display ARHL. By focusing on the phase of dynamic stability prior to the eventual hearing loss we discovered a set of evolutionarily conserved homeostasis genes. The transcription factors Onecut (closest human orthologues: ONECUT2, ONECUT3), Optix (SIX3, SIX6), Worniu (SNAI2) and Amos (ATOH1, ATOH7, ATOH8, NEUROD1) emerged as key regulators, acting upstream of core components of the fly's molecular machinery for auditory transduction and amplification. Adult-specific manipulation of homeostatic regulators in the fly's auditory neurons accelerated-or protected against-ARHL.

Turnover and activity-dependent transcriptional control of NompC in the Drosophila ear

“…Whether such post-translational pools exist and, if so, how they are transported across the cilium and integrated with the existing transcriptional control loops will be one of the key questions of future research into transducer homeostasis. Finally, it is tempting to speculate that a breakdown of homeostasis is the proximate cause for multiple forms of age-related functional decline, such as agerelated hearing loss (Gates and Mills, 2005;Keder et al, 2020). The turnover and activity-dependent transcriptional control of the Drosophila auditory transducer channel NompC reported here will help to address these questions.…”

“…Any change in the density of these auditory TRP channels is thus likely to affect auditory performance, which would suggest a tight regulation. Together with previous molecular inventories of Drosophila hearing (Senthilan et al, 2012) and auditory homeostasis (Keder et al, 2020) these settings form an ideal, low-redundancy model of sensory homeostasis.…”

“…Auditory METs (aMETs) respond to nanometer displacements of their receiver structures (such as stereociliary hair bundles in vertebrate hair cells or antennal sound receivers in Dipteran insects (Albert and Kozlov, 2016)); but, despite the documented presence of proteostasis network (PN) components (Bokolia and Mishra, 2015) required for MET localization (Lee et al, 2008;Park et al, 2013Park et al, , 2015 and the knowledge that larger (Dice et al, 1979) or mechanically loaded (Kjaer et al, 2006) proteins tend to have higher turnover rates, the protein dynamics (and proteostasis) of aMETs is almost entirely unknown. The study of auditory transducer proteostasis is of scientific importance for two reasons: aMETs are (1) the most sensitive type of mechanotransducers, which are, even in the absence of audible sound, constantly flickering between open and closed states, merely responding to the gating forces provided by thermal noise ; (2) they are part of a sensory system that shows substantial age-and noise-dependent vulnerability in both humans (Liberman, 2017;Gates and Mills, 2005) and Drosophila (Christie et al, 2013;Keder et al, 2020). In fact, proteostasis has been recognized as a major factor in aging processes (Taylor and Dillin, 2011;Toyama and Hetzer, 2013).…”

Gene transcription changes in a locust model of noise-induced deafness

“…(33), so the relationship between tympanal movement and sensory response is not straightforward. Aged Drosophila ears had less mechanical gain and reduced stiffness, which was used to predict a 50% reduction in functioning mechanically activated ion channels (7). However, no changes in the passive mechanical structures were recorded.…”

“…Drosophila genes linked to age related deafness(7) with the most similar transcripts from Table1Alternate names for optix are Dmel and Six3. Alternate names for amos are helix-loop-helix, absent MD neurons, reduced olfactory organs, and rough eye.…”