MANF ablation causes prolonged activation of the UPR without neurodegeneration in the mouse midbrain dopamine system

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dc.contributor.author Pakarinen, Emmi
dc.contributor.author Danilova, Tatiana
dc.contributor.author Voikar, Vootele
dc.contributor.author Chmielarz, Piotr
dc.contributor.author Piepponen, Petteri
dc.contributor.author Airavaara, Mikko
dc.contributor.author Saarma, Mart
dc.contributor.author Lindahl, Maria
dc.date.accessioned 2020-08-24T10:37:01Z
dc.date.available 2020-08-24T10:37:01Z
dc.date.issued 2020
dc.identifier.citation Pakarinen , E , Danilova , T , Voikar , V , Chmielarz , P , Piepponen , P , Airavaara , M , Saarma , M & Lindahl , M 2020 , ' MANF ablation causes prolonged activation of the UPR without neurodegeneration in the mouse midbrain dopamine system ' , eNeuro , vol. 7 , no. 1 , ARTN 0477-19.2019 . https://doi.org/10.1523/ENEURO.0477-19.2019
dc.identifier.other PURE: 131468909
dc.identifier.other PURE UUID: a84429fb-f1c4-4e3b-b193-e80d395fe116
dc.identifier.other ORCID: /0000-0002-2318-1612/work/79518138
dc.identifier.other ORCID: /0000-0002-5674-8830/work/79518219
dc.identifier.other ORCID: /0000-0002-2026-1609/work/79518720
dc.identifier.other ORCID: /0000-0003-4201-8666/work/79519680
dc.identifier.other ORCID: /0000-0001-5543-7160/work/79521736
dc.identifier.other WOS: 000562401500038
dc.identifier.uri http://hdl.handle.net/10138/318508
dc.description.abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a lack of MANF from the brain led to the chronic activation of UPR by upregulation of the endoribonuclease activity of the inositol-requiring enzyme 1 alpha (IRE1 alpha) pathway. Furthermore, in the aged MANF-deficient mouse brain in addition the protein kinase-like ER kinase (PERK) and activating transcription factor 6 (ATF6) branches of the UPR pathways were activated. Neuronal loss in neurodegenerative diseases has been associated with chronic ER stress. In our mouse model, increased UPR activation did not lead to neuronal cell loss in the substantia nigra (SN), decrease of striatal dopamine or behavioral changes of MANF-deficient mice. However, cortical neurons lacking MANF were more vulnerable to chemical induction of additional ER stress in vitro. We conclude that embryonic neuronal deletion of MANF does not cause the loss of midbrain dopamine neurons in mice. However, endogenous MANF is needed for maintenance of neuronal ER homeostasis both in vivo and in vitro. en
dc.format.extent 20
dc.language.iso eng
dc.relation.ispartof eNeuro
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject ALZHEIMERS-DISEASE
dc.subject CNS
dc.subject ENDOPLASMIC-RETICULUM STRESS
dc.subject ER STRESS
dc.subject ER stress
dc.subject GENE
dc.subject IMMUNOREACTIVITY
dc.subject KAPPA-B
dc.subject MANF
dc.subject NERVOUS-SYSTEM
dc.subject NEUROTROPHIC FACTOR MANF
dc.subject PARKINSONS-DISEASE
dc.subject UNFOLDED PROTEIN RESPONSE
dc.subject dopamine
dc.subject knock-out mice
dc.subject unfolded protein response
dc.subject 3112 Neurosciences
dc.title MANF ablation causes prolonged activation of the UPR without neurodegeneration in the mouse midbrain dopamine system en
dc.type Article
dc.contributor.organization Institute of Biotechnology
dc.contributor.organization Biosciences
dc.contributor.organization Neuroscience Center
dc.contributor.organization Regenerative pharmacology group
dc.contributor.organization Drug Research Program
dc.contributor.organization Timo Petteri Piepponen / Principal Investigator
dc.contributor.organization University Management
dc.contributor.organization Division of Pharmacology and Pharmacotherapy
dc.contributor.organization Divisions of Faculty of Pharmacy
dc.contributor.organization Helsinki One Health (HOH)
dc.contributor.organization Staff Services
dc.contributor.organization Mart Saarma / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1523/ENEURO.0477-19.2019
dc.relation.issn 2373-2822
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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