Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

Abstract

The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.

Integrated stress response inhibition provides sex-dependent protection against noise-induced cochlear synaptopathy

“…www.nature.com/scientificreports/ astrocyte-derived neurotrophic factor (MANF). In this genetic mouse model, ER stress is associated with loss of synapses in the cochlea, accompanied by progressive hair-cell death and hearing loss 18 . The findings that MANF is cytoprotective in neurons and that Manf inactivation is associated with loss of synapses in the inner ear suggests that the UPR may act similarly in the brain and auditory sensory cells.…”

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

“…A link between UPR-mediated neurodegeneration in the brain, hair-cell loss, and cochlear synaptopathy was suggested by recent work in mice deficient for the ER-stress-regulator mesencephalic astrocyte-derived neurotrophic factor (MANF). In this genetic mouse model, ER stress is associated with loss of synapses in the cochlea, accompanied by progressive hair-cell death and hearing loss 16 . The findings that MANF is cytoprotective in neurons and that Manf inactivation is associated with loss of synapses in the inner ear suggests that the UPR may act similarly in the brain and auditory sensory cells.…”

Impact of Endoplasmic Reticulum Stress in Otorhinolaryngologic Diseases

“…Additionally, a MANF deficiency becomes detrimental when accompanied by gene mutations that predispose to HL, which act by intensifying ER dyshomeostasis. On the basis of these observations, the authors of this study concluded that MANF might serve as a therapeutic candidate for protection against HL induced by stressors that target the ER machinery [36].…”