Neuroplastin Modulates Anti-inflammatory Effects of MANF

Yagi, Takuya; Asada, Rie; Kanekura, Kohsuke; Eesmaa, Ave; Lindahl, Maria; Saarma, Märt; Urano, Fumihiko

doi:10.1016/j.isci.2020.101810

Cited by 51 publications

(54 citation statements)

References 49 publications

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“…Interaction with NPTN was needed for MANF-dependent cell survival and regulation of inflammation. As NPTN is an ER stress–inducible protein, it could account for cultured DA neurons becoming responsive to MANF on ER stress ( 42 ). However, more studies are needed to investigate where exactly do the mechanisms of intracellularly and extracellulary applied MANF converge.…”

Section: Discussionmentioning

confidence: 99%

“…To date, very little is known about the MANF PPIs and their biological functions. We have recently shown neuroplastin (NPTN) to be a plasma membrane receptor for MANF ( 42 ), and another study suggested that the binding of MANF to the plasma membrane is modulated by KDEL endoplasmic reticulum protein retention receptors ( 43 ). In cellular models of multiple epiphyseal dysplasia MANF interacts with a V194D mutant of matrilin-3 that forms non-native disulfide bonds, suggesting that MANF functions as a part of ER stress response with other chaperones ( 36 ).…”

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confidence: 99%

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The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor

Eesmaa

Göös

et al. 2021

Journal of Biological Chemistry

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress–regulated protein exhibiting cytoprotective properties through a poorly understood mechanism in various in vitro and in vivo models of neuronal and non-neuronal damage. Although initially characterized as a secreted neurotrophic factor for midbrain dopamine neurons, MANF has recently gained more interest for its intracellular role in regulating the ER homeostasis, including serving as a cofactor of the chaperone glucose-regulated protein 78 (GRP78). We aimed for a better understanding of the neuroprotective mechanisms of MANF. Here we show for the first time that MANF promotes the survival of ER-stressed neurons in vitro as a general unfolded protein response (UPR) regulator, affecting several UPR pathways simultaneously. Interestingly, MANF does not affect naïve neurons. We hypothesize that MANF regulates UPR signaling toward a mode more compatible with neuronal survival. Screening of MANF interacting proteins from two mammalian cell lines revealed a conserved interactome of 15 proteins including several ER chaperones such as GRP78, GRP170, protein disulfide isomerase family A member 1, and protein disulfide isomerase family A member 6. Further characterization confirmed previously published finding that MANF is a cofactor of GRP78 interacting with its nucleotide binding domain. Using microscale thermophoresis and nuclear magnetic resonance spectroscopy, we discovered that MANF is an ATP binding protein and that ATP blocks the MANF–GRP78 interaction. Interestingly, functional analysis of the antiapoptotic properties of MANF mutants in cultured neurons revealed divergent roles of MANF as a GRP78 cofactor and as an antiapoptotic regulator of UPR. We conclude that the co-factor type interaction with GRP78 is dispensable for the survival-promoting activity of MANF in neurons.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor

Eesmaa

Göös

et al. 2021

Journal of Biological Chemistry

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“…in glia (Langnaese et al 1997). Neuroplastin has been shown to interact as a ligand with the fibroblast growth factor (FGF) receptor (Owczarek et al 2010), gamma-aminobutyric acid type A (GABAA) receptors (Sarto-Jackson et al 2012), S100A8/A9, basigin (Sakaguchi et al 2016;Sumardika et al 2019), mesencephalic astrocyte-derived neurotrophic factor (MANF) (Yagi et al 2020), tumor necrosis factor receptor-associated factor 6 (TRAF6) (Vemula et al 2020), and with itself undergoing homophilic binding (Langnaese et al 1997;Owczarek et al 2010). Furthermore, plasma membrane trafficking of monocarboxylic acid transporter 2 (MCT-2, SLC16A7) and XK-related protein 8 (Xkr8) may require neuroplastin as chaperone (Wilson et al 2013;Suzuki et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Neuroplastin expression is essential for hearing and hair cell PMCA expression

et al. 2021

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Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn−/− mice. Adult Nptn−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn−/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn−/− mice. Conditional ablation of neuroplastin in Nptnlox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult NptnΔlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

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“…While MANF demonstrated potential to rescue cell bodies of dopamine neurons in the substantia nigra (SN) pars compacta (SNpc) in a 6-OHDA rat model, its protective effect on neuronal axons (the fibers of dopamine neurons in the striatum) was modest or absent (Voutilainen et al, 2009(Voutilainen et al, , 2011, making it a dubious NTF candidate for clinical trials in PD patients. However, the fact that MANF mitigates the inflammatory response and ER stress warrants further studies of neurorestorative potential of this NTF in other neurodegenerative diseases (Kovaleva et al, 2020;Yagi et al, 2020).…”

Section: Cerebral Dopamine Neurotrophic Factor (Cdnf)mentioning

confidence: 99%

Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain

Bondarenko

Saarma

2021

Front. Cell. Neurosci.

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Neurotrophic factors (NTFs) are small secreted proteins that support the development, maturation and survival of neurons. NTFs injected into the brain rescue and regenerate certain neuronal populations lost in neurodegenerative diseases, demonstrating the potential of NTFs to cure the diseases rather than simply alleviating the symptoms. NTFs (as the vast majority of molecules) do not pass through the blood–brain barrier (BBB) and therefore, are delivered directly into the brain of patients using costly and risky intracranial surgery. The delivery efficacy and poor diffusion of some NTFs inside the brain are considered the major problems behind their modest effects in clinical trials. Thus, there is a great need for NTFs to be delivered systemically thereby avoiding intracranial surgery. Nanoparticles (NPs), particles with the size dimensions of 1-100 nm, can be used to stabilize NTFs and facilitate their transport through the BBB. Several studies have shown that NTFs can be loaded into or attached onto NPs, administered systemically and transported to the brain. To improve the NP-mediated NTF delivery through the BBB, the surface of NPs can be functionalized with specific ligands such as transferrin, insulin, lactoferrin, apolipoproteins, antibodies or short peptides that will be recognized and internalized by the respective receptors on brain endothelial cells. In this review, we elaborate on the most suitable NTF delivery methods and envision “ideal” NTF for Parkinson’s disease (PD) and clinical trial thereof. We shortly summarize clinical trials of four NTFs, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and cerebral dopamine neurotrophic factor (CDNF), that were tested in PD patients, focusing mainly on GDNF and CDNF. We summarize current possibilities of NP-mediated delivery of NTFs to the brain and discuss whether NPs have impact in improving the properties of NTFs and delivery across the BBB. Emerging delivery approaches and future directions of NTF-based nanomedicine are also discussed.

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Neuroplastin Modulates Anti-inflammatory Effects of MANF

Cited by 51 publications

References 49 publications

The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor

The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor

Neuroplastin expression is essential for hearing and hair cell PMCA expression

Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain

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