Neuroprotective and reparative effects of endoplasmic reticulum luminal proteins – mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor

Albert, Katrina; Airavaara, Mikko

doi:10.3325/cmj.2019.60.99

Cited by 18 publications

(11 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the role of MANF in regulating cerebral ischaemia/reperfusion has been investigated, 15,17,29 the relationship among MANF, UPR and hepatic ischaemia/reperfusion injury has not yet been reported. What makes MANF interesting is that MANF can bypass the translational blockage caused by the UPR, indicating that MANF is associated with coping with the increased levels of unfolded proteins in the ER lumen 30,31 . Previous research also pointed out MANF expression increase is also part of an adaptive and protective pathway in cells 32 .…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte‐derived MANF alleviates hepatic ischaemia‐reperfusion injury via regulating endoplasmic reticulum stress‐induced apoptosis in mice

Yang

Wang

Zhang

et al. 2020

Liver International

View full text Add to dashboard Cite

Background Endoplasmic reticulum (ER) perturbations are novel subcellular effectors involved in the ischaemia‐reperfusion injury. As an ER stress‐inducible protein, mesencephalic astrocyte‐derived neurotrophic factor (MANF) has been proven to be increased during ischaemic brain injury. However, the role of MANF in liver ischaemia reperfusion (I/R) injury has not yet been studied. Methods To investigate the role of MANF in the process of liver ischaemia‐reperfusion, Hepatocyte‐specific MANF knockout (MANFhep−/−) mice and their wild‐type (WT) littermates were used in our research. Mice partial (70%) warm hepatic I/R model was established by vascular occlusion. We detected the serum levels of MANF in both liver transplant patients and WT mice before and after liver I/R injury. Recombinant human MANF (rhMANF) was injected into the tail vein before 1 hour occlusion. AST, ALT and Suzuki score were used to evaluate the extent of I/R injury. OGD/R test was performed on primary hepatocytes to simulate IRI in vitro. RNA sequence and RT‐PCR were used to detect the cellular signal pathway activation while MANF knockout. Results We found that MANF expression and secretion are dramatically up‐regulated during hepatic I/R. Hepatocyte‐specific MANF knockout aggravates the I/R injury through the over‐activated ER stress. The systemic administration of rhMANF before ischaemia has the potential to ameliorate I/R‐triggered UPR and liver injury. Further study showed that MANF deficiency activated ATF4/CHOP and JNK/c‐JUN/CHOP pathways, and rhMANF inhibited the activation of the two proapoptotic pathways caused by MANF deletion. Conclusion Collectively, our study unravels a previously unknown relationship among MANF, UPR and hepatic I/R injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Hepatocyte‐derived MANF alleviates hepatic ischaemia‐reperfusion injury via regulating endoplasmic reticulum stress‐induced apoptosis in mice

Yang

Wang

Zhang

et al. 2020

Liver International

View full text Add to dashboard Cite

show abstract

“…We have discovered a protein with NTF properties, named cerebral dopamine neurotrophic factor (CDNF) [ 20 ], that together with the related mesencephalic astrocyte-derived neurotrophic factor (MANF, also known as ARMET) [ 21 ], form a novel evolutionarily conserved family of unconventional NTFs [ 22 – 27 ]. CDNF and MANF have neurotrophic properties but they otherwise dramatically differ from other known NTFs (Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…CDNF and MANF have neurotrophic properties but they otherwise dramatically differ from other known NTFs (Table 1 ). They have a unique structure, mode of action and they can promote cellular protein homeostasis by regulating ER stress, regulate inflammation and support neuron survival in animal models of PD [ 22 – 27 ]. Surprisingly, variants of CDNF can cross through the BBB thus opening a new possibility for a systemic administration of this neurotrophic drug [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

Lindholm

Saarma

2021

Mol Psychiatry

View full text Add to dashboard Cite

Midbrain dopamine neurons deteriorate in Parkinson’s disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf−/− mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.

show abstract

“…Moreover, CDNF was shown to be effective in the non-human primate 6-OHDA model of PD [100]. The neuroprotective potential of CDNF and MANF has been summarized in recent reviews [101,102]. Overall, CDNF is at least as effective as GDNF [103] with the important advantage of having better diffusion through the brain [96], and in addition to inhibiting neuronal apoptosis, also regulating ER stress and reducing the levels of pro-inflammatory cytokines.…”

Section: Cdnf and Manfmentioning

confidence: 99%

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

Chmielarz

Saarma

2020

Pharmacol. Rep

View full text Add to dashboard Cite

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

show abstract

Neuroprotective and reparative effects of endoplasmic reticulum luminal proteins – mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor

Cited by 18 publications

References 64 publications

Hepatocyte‐derived MANF alleviates hepatic ischaemia‐reperfusion injury via regulating endoplasmic reticulum stress‐induced apoptosis in mice

Hepatocyte‐derived MANF alleviates hepatic ischaemia‐reperfusion injury via regulating endoplasmic reticulum stress‐induced apoptosis in mice

Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

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

Contact Info

Product

Resources

About