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

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http://hdl.handle.net/10138/318508

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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

Titel: MANF ablation causes prolonged activation of the UPR without neurodegeneration in the mouse midbrain dopamine system
Författare: Pakarinen, Emmi; Danilova, Tatiana; Voikar, Vootele; Chmielarz, Piotr; Piepponen, Petteri; Airavaara, Mikko; Saarma, Mart; Lindahl, Maria
Upphovmannens organisation: Institute of Biotechnology
Biosciences
Neuroscience Center
Regenerative pharmacology group
Drug Research Program
Timo Petteri Piepponen / Principal Investigator
University Management
Division of Pharmacology and Pharmacotherapy
Divisions of Faculty of Pharmacy
Helsinki One Health (HOH)
Staff Services
Mart Saarma / Principal Investigator
Datum: 2020
Språk: eng
Sidantal: 20
Tillhör serie: eNeuro
ISSN: 2373-2822
DOI: https://doi.org/10.1523/ENEURO.0477-19.2019
Permanenta länken (URI): http://hdl.handle.net/10138/318508
Abstrakt: 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.
Subject: ALZHEIMERS-DISEASE
CNS
ENDOPLASMIC-RETICULUM STRESS
ER STRESS
ER stress
GENE
IMMUNOREACTIVITY
KAPPA-B
MANF
NERVOUS-SYSTEM
NEUROTROPHIC FACTOR MANF
PARKINSONS-DISEASE
UNFOLDED PROTEIN RESPONSE
dopamine
knock-out mice
unfolded protein response
3112 Neurosciences
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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