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

Pakarinen, Emmi; Danilova, Tatiana; Võikar, Vootele; Chmielarz, Piotr; Piepponen, Petteri; Airavaara, Mikko; Saarma, Märt; Lindahl, Maria

doi:10.1523/eneuro.0477-19.2019

Cited by 27 publications

(39 citation statements)

References 79 publications

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“…MANF is emerging as a crucial protein that is involved in the regulation of ER stress 16,40 . MANF gene knockout studies show an enhancement to cytotoxicity, including caspase‐3 activation and an increase of UPR proteins 41 . In contrast, MANF overexpression in neuronal cells shows the downregulation of UPR proteins such as ATF4 and CHOP 20 .…”

Section: Discussionmentioning

confidence: 99%

Novel mechanism of action for the mood stabilizer lithium

et al. 2020

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Background Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action. Procedure Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein‐1 (AP‐1) inhibitor for 24–72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT‐qPCR. Results In vitro studies showed lithium‐treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP‐1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium‐treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum. Conclusion Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP‐1 transcription factor.

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Section: Discussionmentioning

confidence: 99%

Novel mechanism of action for the mood stabilizer lithium

et al. 2020

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“…MANF-IRE1α crosstalk is further supported by the notion that in MANF knockout mice IRE1α branch of UPR is activated first, and PERK and ATF6 pathways are activated later (Lindahl et al, 2014). Upregulation of spliced XBP1 (sXBP1) downstream to IRE1α was shown to occur first not only for full knockout mice but also for pancreas-specific (Danilova et al, 2019) and for central nervous system-specific MANF ablation (Pakarinen et al, 2020).…”

Section: Introductionmentioning

confidence: 90%

“…MANF is up-regulated in ER stress conditions, bypassing general down-regulation of protein synthesis (Apostolou et al, 2008). MANF has been shown to protect ER stressed cells and alleviate UPR markers in a number of in vitro models (Mizobuchi et al, 2007;Apostolou et al, 2008;Tadimalla et al, 2008;Hellmann et al, 2011;Pakarinen et al, 2020). Recent data also show that MANF is a key regulator of metabolic and immune homeostasis in ageing.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, MANF protects against liver inflammation and fibrosis, suggesting a therapeutic application for MANF in age-related metabolic diseases (Sousa-Victor et al 2019). In MANFdeficient mice UPR pathways are chronically activated in beta cells, in neurons and several other cell types demonstrating that MANF is a crucial regulator of UPR in vivo (Lindahl et al, 2014;Danilova et al, 2019;Pakarinen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α

Kovaleva

Ivanova

et al. 2020

Preprint

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in numerous cell types in vitro and in models of neurodegeneration and diabetes in vivo. So far, the exact mode of its action has remained elusive and plasma membrane or ER-located receptors of MANF have not been identified. We have found that MANF can directly interact with transmembrane unfolded protein response (UPR) receptor IRE1α and compete with the major ER chaperone BiP (GRP78) for the interaction with IRE1α. With lower affinities MANF can also interact with other UPR receptors, PERK and ATF6. Using molecular modeling and mutagenesis analysis, we have identified the exact structural MANF regions involved in its binding to the luminal domain of IRE1α. MANF attenuates UPR signaling by decreasing IRE1α oligomerization and IRE1α phosphorylation. MANF mutant deficient in IRE1α binding cannot regulate IRE1α oligomerization and fails to protect neurons from ER stress induced death. Importantly, we found that MANF-IRE1α interaction is also crucial for the survival promoting action of MANF for dopamine neurons in an animal model of Parkinson's disease. Our data reveal a novel mechanism of IRE1α regulation during ER stress and demonstrate the intracellular mode of action of MANF as a modulator of UPR and neuronal cell survival through the direct interaction with IRE1α and regulation of its activity. Furthermore, our data explain why MANF in contrast to other growth factors has no effects on naive cells and rescues only ER stressed or injured cells.

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“…As for GDNF, probably the most potent and most studied survival promoting NTFs for dopamine neurons, there have been some conflicting results about its necessity for adult dopamine neuron survival [ 105 – 107 ], whereas GDNF receptor RET is widely accepted to be necessary for their adult maintenance [ 108 ]. Interestingly, MANF knockout mice show a normal number of nigrostriatal dopamine neurons and their fibers [ 109 ] but in worms MANF seems to be required for long term maintenance of dopamine neurons [ 110 ]. Also, the MANF-deficient fly [ 111 ] and zebrafish [ 112 ] show defects in the dopamine neuron system.…”

Section: Neurotrophic Factors In Preclinical Studiesmentioning

confidence: 99%

Neurotrophic factors for disease-modifying treatments of Parkinson's disease: gaps between basic science and clinical studies

Chmielarz

Saarma

2020

Pharmacol. Rep

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Background Neurotrophic factors are endogenous proteins promoting the survival of different neural cells. Therefore, they elicited great interest as a possible treatment for neurodegenerative disorders, including Parkinson’s Disease (PD). PD is the second most common neurodegenerative disorder, scientifically characterized more than 200 years ago and initially linked with motor abnormalities. Currently, the disease is viewed as a highly heterogeneous, progressive disorder with a long presymptomatic phase, and both motor and non-motor symptoms. Presently only symptomatic treatments for PD are available. Neurohistopathological changes of PD affected brains have been described more than 100 years ago and characterized by the presence of proteinaceous inclusions known as Lewy bodies and degeneration of dopamine neurons. Despite more than a century of investigations, it has remained unclear why dopamine neurons die in PD. Methods This review summarizes literature data from preclinical studies and clinical trials of neurotrophic factor based therapies for PD and discuss it from the perspective of the current understanding of PD biology. Results Newest data point towards dysfunctions of mitochondria, autophagy-lysosomal pathway, unfolded protein response and prion protein-like spreading of misfolded alpha-synuclein that is the major component of Lewy bodies. Yet, the exact chain of events leading to the demise of dopamine neurons is unclear and perhaps different in subpopulations of patients. Conclusions Gaps in our understanding of underlying disease etiology have hindered our attempts to find treatments able to slow down the progression of PD. Graphic abstract

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

Cited by 27 publications

References 79 publications

Novel mechanism of action for the mood stabilizer lithium

Novel mechanism of action for the mood stabilizer lithium

MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α

Neurotrophic factors for disease-modifying treatments of Parkinson's disease: gaps between basic science and clinical studies

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