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

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Herranen , A , Ikäheimo , K , Lankinen , T , Pakarinen , E , Fritzsch , B , Saarma , M , Lindahl , M & Pirvola , U 2020 , ' Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss ' , Cell Death and Disease , vol. 11 , no. 2 , 100 . https://doi.org/10.1038/s41419-020-2286-6

Title: Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss
Author: Herranen, Anni; Ikäheimo, Kuu; Lankinen, Tuuli; Pakarinen, Emmi; Fritzsch, Bernd; Saarma, Mart; Lindahl, Maria; Pirvola, Ulla
Contributor: University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Institute of Biotechnology
University of Helsinki, Mart Saarma / Principal Investigator
University of Helsinki, Helsinki One Health (HOH)
University of Helsinki, Molecular and Integrative Biosciences Research Programme
Date: 2020-02-06
Language: eng
Number of pages: 12
Belongs to series: Cell Death and Disease
ISSN: 2041-4889
URI: http://hdl.handle.net/10138/314197
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.
Subject: UNFOLDED PROTEIN RESPONSE
NEUROTROPHIC FACTOR MANF
ENDOPLASMIC-RETICULUM
LOCALIZATION
DEAFNESS
MODEL
MICE
1182 Biochemistry, cell and molecular biology
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