A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome

Mahadevan, Jana; Morikawa, Shuntaro; Yagi, Takuya; Abreu, Damien; Lu, Simin; Kanekura, Kohsuke; Brown, Cris M.; Urano, Fumihiko

doi:10.1038/s41374-020-0436-1

Cited by 12 publications

(10 citation statements)

References 51 publications

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“…In addition to diabetes mellitus, cytoprotective effects of MANF have also been shown in animal models of Parkinson disease, ischemia, and retinal neurodegenerative diseases ( Airavaara et al., 2009 ; Glembotski et al., 2012 ; Lu et al., 2018 ; Neves et al., 2016 ; Voutilainen et al., 2009 ). Furthermore, we have recently reported that MANF prevents ER stress-mediated β-cell death in cell and mouse models of Wolfram syndrome ( Mahadevan et al., 2020 ). These previous reports and our findings indicate that screening assays, such as surface plasmon resonance (SPR), to discover small molecules that bind to NPTN and mediate survival and anti-inflammatory effects will lead to a novel therapeutic strategy for a variety of ER stress-related diseases, including diabetes, neurodegeneration, retinal degeneration, and Wolfram syndrome ( Abreu and Urano, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Neuroplastin Modulates Anti-inflammatory Effects of MANF

et al. 2020

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Summary Endoplasmic reticulum (ER) stress is known to induce pro-inflammatory response and ultimately leads to cell death. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER-localized protein whose expression and secretion is induced by ER stress and a crucial survival factor. However, the underlying mechanism of how MANF exerts its cytoprotective activity remains unclear due to the lack of knowledge of its receptor. Here we show that Neuroplastin (NPTN) is such a receptor for MANF. Biochemical analysis shows the physiological interaction between MANF and NPTN on the cell surface. Binding of MANF to NPTN mitigates the inflammatory response and apoptosis via suppression of NF-kβ signaling. Our results demonstrate that NPTN is a cell surface receptor for MANF, which modulates inflammatory responses and cell death, and that the MANF-NPTN survival signaling described here provides potential therapeutic targets for the treatment of ER stress-related disorders, including diabetes mellitus, neurodegeneration, retinal degeneration, and Wolfram syndrome.

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Section: Discussionmentioning

confidence: 99%

Neuroplastin Modulates Anti-inflammatory Effects of MANF

et al. 2020

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“…MANF [81] no Stimulating proliferation and alleviating ER stress [81] Akt activators no Potentially inducing proliferation and survival by stimulating Akt pathway [80] Curr Opin Physiol. Author manuscript; available in PMC 2021 October 01.…”

Section: Discussionmentioning

confidence: 99%

“…For this purpose, restoring Akt activity in WS may be a promising new avenue [24, 53,80]. Similarly, it has been reported that mesencephalic astrocyte-derived neurotrophic factor (MANF) can enhance the proliferation of remaining β cells in WS mice [81].…”

Section: Regenerative Medicinementioning

confidence: 99%

Wolfram syndrome: a monogenic model for diabetes mellitus and neurodegeneration

Fischer

Ehrlich

2020

Current Opinion in Physiology

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Wolfram syndrome (WS) is a rare, progressive disorder characterized by childhood-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and neurodegeneration. Currently, there is no effective treatment for WS, and patients typically die between 30 and 40 years of age. WS is primarily caused by autosomal recessive mutations in the Wolfram syndrome 1 (WFS1) gene (OMIM 222300), which encodes for wolframin (WFS1). This disorder is therefore a valuable monogenic model for prevalent diseases, particularly diabetes mellitus and neurodegeneration. Whereas reduced survival and secretion are known cellular impairments causing WS, the underlying molecular pathways and the physiological function of WFS1 remain incompletely described. Here, we characterize WFS1 as a regulator of intracellular calcium homeostasis, review our current understanding of the disease mechanism of WS, and discuss candidate treatment approaches. These insights will facilitate identification of new therapeutic strategies not only for WS but also for diabetes mellitus and neurodegeneration.

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“…MANF is involved in protein homeostasis as it is upregulated upon ER stress, interacts with BiP and is secreted upon ER Ca 2+ depletion (Glembotski et al, 2012;Petrova et al, 2003). As MANF has pleiotropic actions in regulating ER homeostasis factors, including the UPR and Ca 2+ channels, it has been studied also extensively as a therapeutic approach for many ER stress related diseases, such as Wolfram disease, diabetes, stroke, hearing loss and Parkinson's disease (Airavaara et al, 2010;Airavaara et al, 2009;Albert and Airavaara, 2019;Glembotski et al, 2012;Herranen et al, 2020;Lindahl et al, 2014;Mahadevan et al, 2020;Voutilainen et al, 2015;Voutilainen et al, 2009).…”

Section: Downloaded Frommentioning

confidence: 99%

Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases

et al. 2023

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The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca 2+ ) and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca 2+ level in the ER lumen and low cytosolic concentration is needed for Ca 2+based intracellular signaling, also for synaptic signaling and Ca 2+ waves, as well as preparing proteins for correct folding in the presence of high Ca 2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca 2+ is controlled in axodendritic areas for proper neurito-and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiological functions of the neuronal ER and discuss it in context of common neurodegenerative diseases focusing on pharmacological regulation of ER Ca 2+ . Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity and ensuring Ca 2+ regulation is a crucial factor for the aging and selective vulnerability of neurons in various neurodegenerative diseases.Significance statement ER Ca 2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca 2+ can provide restoration of protein homeostasis, e.g. folding of complex plasma membrane signalling receptors and slow down the degeneration process of neurons.

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A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome

Cited by 12 publications

References 51 publications

Neuroplastin Modulates Anti-inflammatory Effects of MANF

Neuroplastin Modulates Anti-inflammatory Effects of MANF

Wolfram syndrome: a monogenic model for diabetes mellitus and neurodegeneration

Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases

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