Trophic activities of endoplasmic reticulum proteins CDNF and MANF

Jäntti, Maria; Harvey, Brandon K.

doi:10.1007/s00441-020-03263-0

Cited by 43 publications

(35 citation statements)

References 136 publications

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“…The presence of KDEL receptors at the cell surface has been reported, suggesting a multifaceted role for KDEL receptors. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-responsive protein with an ERS [ 20 ]. Henderson et al, 2013, demonstrated that ER calcium depletion increased the cell surface KDEL receptor expression and indicated MANF interaction with KDEL receptors at the cell surface [ 21 ].…”

Section: Kdel Retrieval Pathway and Kdel Receptorsmentioning

confidence: 99%

The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein misfolding and activation of the unfolded protein response (UPR). Additionally, ER resident proteins are secreted from the cell by overwhelming the KDEL receptor retrieval pathway. Recent data show that KDEL receptors are also activated during the UPR through the IRE1/XBP1 signaling pathway as an adaptive response to cellular stress set forth to reduce the loss of ER resident proteins. This review will discuss the emerging connection between UPR activation and KDEL receptors as it pertains to ER proteostasis and disease states.

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Section: Kdel Retrieval Pathway and Kdel Receptorsmentioning

confidence: 99%

The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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“…Thus, MANF and CDNF are potent factors, providing protection and enhancing the repair of DA neurons. Although the mechanisms underlying the neuroprotective effects of CDNF and MANF are not well understood, these proteins are thought to be involved in the regulation of endoplasmic reticulum (ER) function and homeostasis [41,42]. Both proteins uniquely contain an N-terminal signal peptide that directs them to the ER and a C-terminal KDEL-like ER-retention signal.…”

Section: Release Of Neurotrophic Factorsmentioning

confidence: 99%

“…Both CDNF and MANF act as modulators of UPR. Furthermore, recent studies have demonstrated the anti-inflammatory role of CDNF and MANF; these proteins antagonize the secretion of pro-inflammatory factors such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α [42].…”

Section: Release Of Neurotrophic Factorsmentioning

confidence: 99%

Neuron-Astrocyte Interactions in Parkinson’s Disease

Miyazaki

Asanuma

2020

Cells

101

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

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“…Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) represent a family of novel, evolutionary conserved proteins [ 1 ]. MANF and CDNF reside in the endoplasmic reticulum (ER) lumen and are involved in ER homeostasis and stress response [ 2 ]. They are classified as separate family of neurotrophic factors and are extensively studied due to their protective activity [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs

Konovalova

Gerasymchuk

Arroyo

et al. 2021

IJMS

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Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is known about the control of their expression. miRNAs—small non-coding RNAs—are important regulators of gene expression. Their dysregulation was demonstrated in multiple pathological processes and their ability to modulate levels of other neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was previously reported. Here, for the first time we demonstrated direct regulation of MANF and CDNF by miRNAs. Using bioinformatic tools, reporter assay and analysis of endogenous MANF and CDNF, we identified that miR-144 controls MANF expression, and miR-134 and miR-141 downregulate CDNF levels. We also demonstrated that this effect is human-specific and is executed via predicted binding sites of corresponding miRNAs. Finally, we found that miR-382 suppressed hCDNF expression indirectly. In conclusion, we demonstrate for the first time direct regulation of MANF and CDNF expression by specific miRNAs, despite the fact their binding sites are not strongly evolutionary conserved. Furthermore, we demonstrate a functional effect of miR-144 mediated regulation of MANF on ER stress response markers. These findings emphasize that (1) prediction of miRNA targets based on evolutionary conservation may miss biologically meaningful regulatory pairs; and (2) interpretation of miRNA regulatory effects in animal models should be cautiously validated.

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Trophic activities of endoplasmic reticulum proteins CDNF and MANF

Cited by 43 publications

References 136 publications

The Function of KDEL Receptors as UPR Genes in Disease

The Function of KDEL Receptors as UPR Genes in Disease

Neuron-Astrocyte Interactions in Parkinson’s Disease

Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs

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