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

Show simple item record

dc.contributor.author Herranen, Anni
dc.contributor.author Ikäheimo, Kuu
dc.contributor.author Lankinen, Tuuli
dc.contributor.author Pakarinen, Emmi
dc.contributor.author Fritzsch, Bernd
dc.contributor.author Saarma, Mart
dc.contributor.author Lindahl, Maria
dc.contributor.author Pirvola, Ulla
dc.date.accessioned 2020-04-20T10:23:03Z
dc.date.available 2020-04-20T10:23:03Z
dc.date.issued 2020-02-06
dc.identifier.citation 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
dc.identifier.other PURE: 135691944
dc.identifier.other PURE UUID: b3063351-e915-47f5-a9fd-c7fd184ed725
dc.identifier.other WOS: 000513500600005
dc.identifier.other ORCID: /0000-0002-5674-8830/work/72779267
dc.identifier.other ORCID: /0000-0001-5543-7160/work/72782810
dc.identifier.uri http://hdl.handle.net/10138/314197
dc.description.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. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Cell Death and Disease
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject UNFOLDED PROTEIN RESPONSE
dc.subject NEUROTROPHIC FACTOR MANF
dc.subject ENDOPLASMIC-RETICULUM
dc.subject LOCALIZATION
dc.subject DEAFNESS
dc.subject MODEL
dc.subject MICE
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss en
dc.type Article
dc.contributor.organization Molecular and Integrative Biosciences Research Programme
dc.contributor.organization Institute of Biotechnology
dc.contributor.organization Mart Saarma / Principal Investigator
dc.contributor.organization Helsinki One Health (HOH)
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1038/s41419-020-2286-6
dc.relation.issn 2041-4889
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

Files in this item

Total number of downloads: Loading...

Files Size Format View
s41419_020_2286_6.pdf 17.14Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record