Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Elevates Stimulus-Evoked Release of Dopamine in Freely-Moving Rats

Renko, Juho‐Matti; Bäck, Susanne; Voutilainen, Merja H.; Piepponen, Petteri; Reenilä, Ilkka; Saarma, Märt; Tuominen, Raimo K.

doi:10.1007/s12035-018-0872-8

Cited by 12 publications

(9 citation statements)

References 71 publications

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“…Further research on the exact mechanisms of α-syn clearance will help understand the neuroprotective role of IRE1. Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as ARMET (arginine-rich mutated in early-stage tumors) is present in ER and promotes neuronal cell survival through UPR regulation (Apostolou et al, 2008;Renko et al, 2018;Wang et al, 2021). ER stress triggers the accumulation of misfolded α-syn (Colla et al, 2012a).…”

Section: Mechanism Of Neuronal Clearance Of Misfolded α-Synuclein By Autophagymentioning

confidence: 99%

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Ray

Mahalakshmi

Tuladhar

et al. 2021

Front. Cell Dev. Biol.

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Parkinson’s disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut–brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.

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Section: Mechanism Of Neuronal Clearance Of Misfolded α-Synuclein By Autophagymentioning

confidence: 99%

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Ray

Mahalakshmi

Tuladhar

et al. 2021

Front. Cell Dev. Biol.

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“…Consistent with our findings, among the 26 proteins significantly influenced by VB, we identified MANF, an ER stress response protein. As a member of the fourth family of neurotrophic factors, MANF has been proven to protect and repair dopaminergic neurons and maintain the homeostasis of ER proteins [42,43]. According to our STRING protein interaction mapping analysis, MANF is found to interact with ATF4, XBP1, and ATF6.…”

Section: Discussionmentioning

confidence: 94%

“…4 f). MANF is a key factor in alleviating ER stress and maintaining ER homeostasis [ 42 ] and has been confirmed to be upregulated during ER stress and can resist Aβ toxicity by attenuating Aβ-induced ER stress [ 43 ]. In the hippocampus of APP/PS1 mice, VB decreased the expression levels of MANF, suggesting that VB protected against ER stress (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neuroprotective effects of verbascoside against Alzheimer’s disease via the relief of endoplasmic reticulum stress in Aβ-exposed U251 cells and APP/PS1 mice

Wang

Cai

Wang

et al. 2020

J Neuroinflammation

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Background Endoplasmic reticulum (ER) stress is involved in the progression of Alzheimer’s disease (AD). Verbascoside (VB), an active phenylethanoid glycoside that was first isolated from Verbascum sinuatum (the wavyleaf mullein), possesses anti-inflammatory, antioxidative, and anti-apoptotic effects. The purpose of this study was to elucidate the beneficial effects of VB in amyloid β (Aβ)1–42-damaged human glioma (U251) cells and in APPswe/PSEN1dE9 transgenic (APP/PS1) mice. Methods U251 cells were co-incubated with 10 μM of Aβ1-42 and treated with VB. The protective effects of VB were investigated by using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, fluorescence staining, and transmission electron microscopy. APP/PS1 transgenic mice were treated for 6 weeks with VB. Learning and memory were evaluated using a Morris water maze test. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, thioflavin-S staining, and proteomics analysis were performed to study the potential neuroprotective mechanism. Enzyme-linked immunosorbent assays and western blot were performed to analyze altered protein levels of brain lysates in APP/PS1 mice and/or Aβ1-42-damaged U251 cells. Results In Aβ1-42-damaged U251 cells, VB significantly improved cell viability, inhibited apoptosis, reduced calcium accumulation and the intracellular concentrations of reactive oxygen species, and improved the morphology of mitochondria and ER. In APP/PS1 mice, 6-week administration of VB significantly improved memory and cognition. VB inhibited apoptosis, reduced the deposition of Aβ, reduced the formation of neurofibrillary tangles formed by hyperphosphorylated tau protein, and downregulated the expression levels of 4-hydroxynonenal and mesencephalic astrocyte-derived neurotrophic factor in the brains of APP/PS1 mice. Proteomics analysis of mouse hippocampus suggested that the neuroprotective effect of VB may be related to the reduction of ER stress. This was indicated by the fact that VB inhibited the three branches of the unfolded protein response, thereby attenuating ER stress and preventing apoptosis. Conclusions The results confirmed that VB possesses significant neuroprotective effects, which are related to the reduction of ER stress. These findings support the status of VB as a potentially effective treatment for AD and warrant further research.

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“…In a rat model of Parkinson's disease, MANF can protect rat's tyrosine hydroxylase-positive cells against 6-OHDA induced damage [37], another in vitro studies results suggested that MANF exert neuroprotective role in SH-SY5Y cells after damaged by 6-OHDA [9,38]. Moreover, a recent study indicated that MANF promoted the secretion of dopamine under the injection of MANF into rat striatum [39]. Therefore, it may imply that the potential therapeutic role of MANF in Parkinson's disease.…”

Section: Cytoprotective Role Of Manfmentioning

confidence: 97%

Potential Therapeutic Role and Mechanism of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Metabolic Disease

Ltd¹

2020

DWMJ

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Metabolic disease is a global epidemic and gradually became a serious public health problem, which comprised a few similar metabolic disorders such as obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Metabolic diseases are characterized by the accumulation of abundant nutrients, subsequently induce glucolipotoxicity, intracellular stress, inflammation, and ultimately cell damage. Endoplasmic Reticulum stress (ER stress) exerts an important role in the pathogenesis of metabolic disease. ER stress could induce the inflammation and insulin resistance in adipocytes and hepatocytes, increase the apoptosis of pancreatic β cells and hepatocytes, and promote the gluconeogenesis and fatty acids synthesis. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF) are the newly discovered Neurotrophic Factors (NTFs), which are firstly discovered for the neuroprotective functions. Both MANF and CDNF have a similar structure, but emerging evidence showed the prominent metabolic effect of MANF. MANF is also a secreted protein, located in the endoplasmic reticulum and ER stress would induce its expression and secretion. MANF is involved in food intake and the proliferation and survival of pancreatic β cells. Furthermore, MANF can protect hepatocyte against metabolic stress damage. Regards that the potential role of MANF in metabolic disease and ER stress, in this review, we summarized the molecular structure, physiological function and potential therapeutic role and mechanism of MANF in metabolic diseases.

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Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Elevates Stimulus-Evoked Release of Dopamine in Freely-Moving Rats

Cited by 12 publications

References 71 publications

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease

Neuroprotective effects of verbascoside against Alzheimer’s disease via the relief of endoplasmic reticulum stress in Aβ-exposed U251 cells and APP/PS1 mice

Potential Therapeutic Role and Mechanism of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Metabolic Disease

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