Poststroke delivery of MANF promotes functional recovery in rats

Mätlik, Kert; Anttila, Jenni E.; Tseng, Kuan-Yin; Smolander, Olli‐Pekka; Pakarinen, Emmi; Lehtonen, Leevi; Abo‐Ramadan, Usama; Lindholm, Päivi; Zheng, Congjun; Harvey, Brandon K.; Arumäe, Urmas; Lindahl, Maria; Airavaara, Mikko

doi:10.1126/sciadv.aap8957

Cited by 65 publications

(87 citation statements)

References 30 publications

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“…. Other studies also demonstrate expression of MANF by myeloid cells (Neves et al, 2016;Mätlik et al, 2018). It is possible that MANF is expressed by microglia in our Manf fl/fl ::Nestin Cre/1 mice.…”

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confidence: 52%

“…We have shown that exogenously administered MANF before cerebral ischemia protects cortical neurons in rats (Airavaara et al, 2009) and poststroke delivery of MANF induces functional recovery of rats after cerebral ischemia (Mätlik et al, 2018). Moreover, the infarction size in the MANF-deficient brain is larger, indicating that endogenous MANF has a protective effect on cortical neurons against ischemic injury (Mätlik et al, 2018). Therefore, we examined ER stress in the Manf -/primary cortical neurons.…”

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confidence: 99%

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MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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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

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confidence: 52%

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confidence: 99%

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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“…Cellular count for MANF/BrdU positive cells is presented in Figure 6C. The number of MANF/BrdU + cells was increased in DHA-treated rats compared to saline-treated rats in peri-infarct cortex and DG on Day 14. ing ischemic stroke increased the quantity of phagocytic microglia at 4 days in the peri-infarct region, 31,32 and rhMANF promoted neuron proliferation and prevented neuronal apoptosis. 33 Our study found that MANF was upregulated in neurons and The microglia cell surface receptor TREM2 is highly expressed in response to neuronal cell damage, and its decreased abundance inhibits prolonged phagocytic microglial activity following injury.…”

Section: Dha Improves Long-term Survival Attenuates Infarct Sizementioning

confidence: 89%

DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke

et al. 2020

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Aims: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a secretory neurotrophic factor protein that promotes repair after neuronal injury. The microglia cell surface receptor (triggering receptor expressed on myeloid cells-2; TREM2) regulates the production of pro-and antiinflammatory mediators after stroke. Here, we study MANF and TREM2 expression after middle cerebral artery occlusion (MCAo) and explore if docosahexaenoic acid (DHA) treatment exerts a potentiating effect. Methods: We used 2 hours of the MCAo model in rats and intravenously administered DHA or vehicle at 3 hours after the onset of MCAo. Neurobehavioral assessment was performed on days 1, 3, 7, and 14; MANF and TREM2 expression was measured by immunohistochemistry and Western blotting. Results: MANF was upregulated in neurons and astrocytes on days 1, 7, and 14, and TREM2 was expressed on macrophages in the ischemic penumbra and dentate gyrus (DG) on days 7 and 14. DHA improved neurobehavioral recovery, attenuated infarct size on days 7 and 14, increased MANF and decreased TREM2 expression in ischemic core, penumbra, DG, and enhanced neurogenesis on Day 14. Conclusion: MANF and TREM2 protein abundance is robustly increased after MCAo, and DHA treatment potentiated MANF abundance, decreased TREM2 expression, improved neurobehavioral recovery, reduced infarction, and provided enhanced neuroprotection.

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“…Indeed, when applied to the animals with severe chemically induced Parkinsonian symptoms, these factors significantly improve the neurological scores and reduce histological brain damages ( Lindholm et al, 2007 ; Airavaara et al, 2009 ; Voutilainen et al, 2009 , 2011 ; Huotarinen et al, 2018 ). MANF is also neurorestorative in the rat model of cerebral stroke ( Matlik et al, 2018 ). The cytoprotective mechanisms of MANF and CDNF are currently poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

Božok

Palgi

et al. 2018

Front. Cell Dev. Biol.

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a potent survival-promoting protein with neurorestorative effect for neurodegenerative diseases. Its mechanism of action, albeit poorly known, depends strongly on the CXXC motif (CKGC). Here we studied the survival-promoting properties of the CKGC tetrapeptide from MANF. In the Jurkat T lymphocytic cell line, CKGC potently inhibits death receptor Fas-induced apoptosis and mildly counteracts mitochondrial apoptosis and necroptosis. The peptide with serines instead of cysteines (SKGS) has no survival-promoting activity. The cytoprotective efficiency of the peptide against Fas-induced apoptosis is significantly improved by reduction of its cysteines by dithiotreitol, suggesting that it protects the cells via cysteine thiol groups, partially as an antioxidant. CKGC neutralizes the reactive oxygen species, maintains the mitochondrial membrane potential and prevents activation of the effector caspases in the Jurkat cells with activated Fas. The peptide does not require intracellular administration, as it is endocytosed and resides mainly in the Golgi. Finally, the peptide also potently promotes survival of cultured primary dopaminergic neurons.

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Poststroke delivery of MANF promotes functional recovery in rats

Abstract: Delayed delivery of MANF to rat brain after ischemic stroke promotes functional recovery and recruits phagocytic immune cells.

Cited by 65 publications

References 30 publications

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke

Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

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