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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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE148023 | GEO | 2020/04/03

REPOSITORIES: GEO

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Project description:We performed a microarray analysis of auditory midbrain (inferior colliculus, IC) mRNA from young adult CBA mice (controls) with good hearing, middle aged (MA) with good hearing, and old mild (MP) and severe (SP) presbycusic CBA mice. Fold Change data derived from RMA normalization revealed that the overall GABA receptor alpha 6 expression profiles for MA, MP and SP were down-regulated relative to young adult controls with good hearing. Relative real-time PCR for five GABA receptors confirmed this age-related down regulation quantitatively. Functional hearing data: Auditory Brainstem Responses (ABR) enriched the analysis to select the probe-sets that changed with age and hearing loss by the linear regression best-fit line model technique. GABA receptor genotype-phenotype correlations with auditory functional data indicated that GABA-receptor subtypes are under expressed in SP mice. Hierarchical clustering (HC) analyses yielded statistical significance of normalized GeneChip data Real-time PCR showed that Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1 may be involved in physiological changes that occur in age-related hearing loss. Presbycusis – age-related hearing loss – is the number one communicative disorder of our aged population. In this study we analyzed gene expression for a set of GABA receptors in the inferior colliculus of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing changes from RMA normalized microarray data (39 replicates) in four age-groups, Young Controls and Middle aged mice with good hearing, mild and sever e presbycusis from old mice. Fold change gene expression derived from RMA normalized data were first subjected to one-way ANOVA, and then linear regression was performed. The selected gene expression changes were confirmed by relative real-time relative to young adult controls with good hearing. Statistically significant and real time PCR confirmed GABA receptor genes; Gabra6, GABA B receptor 1 (Gabbr1), and Gaba transporter protein Slc32a1, may be involved in physiological changes that occur in age-related hearing loss. Lastly, gene expression measures of each age group were correlated with pathway/network relationships relevant to the inferior colliculus using Pathway Architect, to identify key pathways consistent with the gene expression changes observed In the study of Expression changes in IC GABA receptors in the Auditory Midbrain of young adult and aging presbycusis mice total of thirty nine chips were used. The normal aging mice were in Four groups Young adults Controls with good hearing (8 mice, 8 MOE430A GeneChips), Middle aged group with good hearing ( 17 mice, 17 MOE430A GeneChips), Mild Presbycusis with limited hearing loss (9 mice, 9 MOE430A GeneChips) and Severe Presbycusis (5 mice, 5 MOE430A GeneChips).

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

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