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Cell Reports Feb 2023Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic β...
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic β cells in vitro and in models of neurodegeneration and diabetes in vivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1α, and we identify the binding interface between MANF and IRE1α. The expression of wild-type MANF, but not its IRE1α binding-deficient mutant, attenuates UPR signaling by decreasing IRE1α oligomerization; phosphorylation; splicing of Xbp1, Atf6, and Txnip levels; and protecting neurons from ER stress-induced death. MANF-IRE1α interaction and not MANF-BiP interaction is crucial for MANF pro-survival activity in neurons in vitro and is required to protect dopamine neurons in an animal model of Parkinson's disease. Our data show IRE1α as an intracellular receptor for MANF and regulator of neuronal survival.
Topics: Animals; Endoribonucleases; Protein Serine-Threonine Kinases; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Nerve Growth Factors; Dopaminergic Neurons
PubMed: 36739529
DOI: 10.1016/j.celrep.2023.112066 -
International Journal of Molecular... Jan 2020Diabetes and its chronic complications still represent a great clinical problem, despite improvements made in the diagnosis and treatment of the disease. People with... (Review)
Review
Diabetes and its chronic complications still represent a great clinical problem, despite improvements made in the diagnosis and treatment of the disease. People with diabetes have a much higher risk of impaired brain function and psychiatric disorders. Neurotrophins are factors that protect neuronal tissue and improve the function of the central nervous system, and among them is brain-derived neurotrophic factor (BDNF). The level and function of BDNF in diabetes seems to be disturbed by and connected with the presence of insulin resistance. On the other hand, there is evidence for the highly beneficial impact of physical activity on brain function and BDNF level. However, it is not clear if this protective phenomenon works in the presence of diabetes. In this review, we summarize the current available research on this topic and find that the results of published studies are ambiguous.
Topics: Brain-Derived Neurotrophic Factor; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Humans; Insulin Resistance; Nerve Growth Factors
PubMed: 32012942
DOI: 10.3390/ijms21030841 -
Current Allergy and Asthma Reports Feb 2018Asthma is a chronic airway disease that affects more than 300 million people worldwide. Current treatment focuses on symptomatic relief by temporally dampening... (Review)
Review
PURPOSE OF REVIEW
Asthma is a chronic airway disease that affects more than 300 million people worldwide. Current treatment focuses on symptomatic relief by temporally dampening inflammation and relaxing the airway. Novel combative strategies against asthma and hopefully a cure are yet to be developed. The goal of this review is to summarize recent literature on neurotrophins (NTs) in experimental models and clinical settings of asthma research.
RECENT FINDINGS
We highlight studies of early phases of asthma that collectively reveal a profound impact of elevated NT levels following initial detrimental insults on long-term airway dysfunction. We hope this review will foster insights into the complex interaction between NTs, nerves, immune cells, and airway structural cells during a critical time window of development and disease susceptibility. Future studies are required to better understand the role of NTs in asthma pathophysiology and to evaluate whether NTs and their receptors may serve as new drug targets.
Topics: Animals; Asthma; Brain-Derived Neurotrophic Factor; Humans; Nerve Growth Factors
PubMed: 29453651
DOI: 10.1007/s11882-018-0765-y -
Molecular Psychiatry Mar 2022Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the... (Review)
Review
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.
Topics: Animals; Dopamine; Dopaminergic Neurons; Glial Cell Line-Derived Neurotrophic Factor; Mammals; Mice; Nerve Growth Factors; Parkinson Disease; Unfolded Protein Response
PubMed: 34907395
DOI: 10.1038/s41380-021-01394-6 -
International Journal of Molecular... Apr 2022To date, no studies have addressed the role of neurotrophins (NTs) in spp. infections in the brain. Thus, to clarify the role of NTs in the cerebral cortex and...
To date, no studies have addressed the role of neurotrophins (NTs) in spp. infections in the brain. Thus, to clarify the role of NTs in the cerebral cortex and hippocampus during experimental acanthamoebiasis in relation to the host immune status, the purpose of this study was to determine whether spp. may affect the concentration of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in brain structures. Our results suggest that at the beginning of infection in immunocompetent hosts, BDNF and NT-3 may reflect an endogenous attempt at neuroprotection against spp. infection. We also observed a pro-inflammatory effect of NGF during acanthamoebiasis in immunosuppressed hosts. This may provide important information for understanding the development of cerebral acanthamoebiasis related to the immunological status of the host. However, the pathogenesis of brain acanthamoebiasis is still poorly understood and documented and, therefore, requires further research.
Topics: Acanthamoeba; Amebiasis; Brain; Brain-Derived Neurotrophic Factor; Humans; Nerve Growth Factor; Nerve Growth Factors; Neurotrophin 3
PubMed: 35563321
DOI: 10.3390/ijms23094931 -
Cells Mar 2023Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a member of the new family of neurotrophic factors (NTFs) with a unique structure and functions compared to... (Review)
Review
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a member of the new family of neurotrophic factors (NTFs) with a unique structure and functions compared to other conventionally known NTFs. MANF is broadly expressed in developing and mature tissues, including the central nervous system and peripheral nervous system tissues. Growing research demonstrated that MANF protects neurons from endoplasmic reticulum (ER) stress-associated complications by restoring ER homeostasis and regulating unfolded protein response. This review discusses MANF signaling in neurodegenerative conditions with specific emphasis given to its overall effect and mechanisms of action in experimental models of Parkinson's disease, Alzheimer's disease, and stroke. Additional perspectives on its potential unexplored roles in other neurodegenerative conditions are also given.
Topics: Animals; Humans; Nerve Growth Factors; Neurodegenerative Diseases; Endoplasmic Reticulum Stress; Stroke; Signal Transduction
PubMed: 37048105
DOI: 10.3390/cells12071032 -
Human Reproduction Update Mar 2019Neurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)] and glial cell line-derived... (Review)
Review
BACKGROUND
Neurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)] and glial cell line-derived neurotrophic factor (GDNF) are soluble polypeptide growth factors that are widely recognized for their roles in promoting cell growth, survival and differentiation in several classes of neurons. Outside the nervous system, neurotrophin (NT) and GDNF signaling events have substantial roles in various non-neural tissues, including the ovary.
OBJECTIVE AND RATIONALE
The molecular mechanisms that promote and regulate follicular development and oocyte maturation have been extensively investigated. However, most information has been obtained from animal models. Even though the fundamental process is highly similar across species, the paracrine regulation of ovarian function in humans remains poorly characterized. Therefore, this review aims to summarize the expression and functional roles of NTs and GDNF in human ovarian biology and disorders, and to describe and propose the development of novel strategies for diagnosing, treating and preventing related abnormalities.
SEARCH METHODS
Relevant literature in the English language from 1990 to 2018 describing the role of NTs and GDNF in mammalian ovarian biology and phenotypes was comprehensively selected using PubMed, MEDLINE and Google Scholar.
OUTCOMES
Studies have shown that the neurotrophins NGF, BDNF, NT-3 and NT-4 as well as GDNF and their functional receptors are expressed in the human ovary. Recently, gathered experimental data suggest putative roles for NT and GDNF signaling in the direct control of ovarian function, including follicle assembly, activation of the primordial follicles, follicular growth and development, oocyte maturation, steroidogenesis, ovulation and corpus luteum formation. Additionally, crosstalk occurs between these ovarian regulators and the endocrine signaling system. Dysregulation of the NT system may negatively affect ovarian function, leading to reproductive pathology (decreased ovarian reserve, polycystic ovary syndrome and endometriosis), female infertility and even epithelial ovarian cancers.
WIDER IMPLICATIONS
A comprehensive understanding of the expression, actions and underlying molecular mechanisms of the NT/GDNF system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in ovarian diseases and to develop more safe, effective methods of inducing ovulation in ART in the treatment of female infertility.
Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Communication; Female; Glial Cell Line-Derived Neurotrophic Factor; Humans; Nerve Growth Factor; Nerve Growth Factors; Neurotrophin 3; Oogenesis; Ovarian Follicle; Ovulation; Signal Transduction
PubMed: 30608586
DOI: 10.1093/humupd/dmy047 -
Neurogastroenterology and Motility Oct 2018Neurotrophic factors are traditionally recognized for their roles in differentiation, growth, and survival of specific neurons in the central and peripheral nervous... (Review)
Review
Neurotrophic factors are traditionally recognized for their roles in differentiation, growth, and survival of specific neurons in the central and peripheral nervous system. Some neurotrophic factors are essential for the development and migration of the enteric nervous system along the fetal and post-natal gut. Over the last two decades, several non-developmental functions of neurotrophic factors have been characterized. In the adult gastrointestinal tract, neurotrophic factors regulate gut sensation, motility, epithelial barrier function, and protect enteric neurons and glial cells from damaging insults in the microenvironment of the gut. In this issue of Neurogastroenterology and Motility, Fu et al demonstrate that brain-derived neurotrophic factor plays a role in the pathogenesis of distention-induced abdominal pain in bowel obstruction. In light of this interesting finding, this mini-review highlights some of the recent advances in understanding of the physiological and pathophysiological roles of neurotrophic factors in the adult gut.
Topics: Animals; Enteric Nervous System; Humans; Nerve Growth Factors
PubMed: 30259610
DOI: 10.1111/nmo.13446 -
Trends in Endocrinology and Metabolism:... Apr 2022Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum-resident protein and a secretory factor and has beneficial effects in multiple... (Review)
Review
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum-resident protein and a secretory factor and has beneficial effects in multiple diseases. Recent evidence shows that its circulating levels in humans are dynamically regulated under various metabolic diseases, including diabetes, obesity, fatty liver, and cardiovascular diseases, suggesting that MANF may play a role in these pathological states. Also, its downregulation in mice impairs glucose homeostasis, promotes lipid accumulation in the liver, reduces energy expenditure, and induces inflammation. Conversely, MANF overexpression prevents or mitigates some of these metabolic disturbances. In particular, systemic MANF administration alleviates dietary obesity and related metabolic disorders in obese mice. We therefore propose that MANF might be a promising target for treating chronic metabolic diseases.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Metabolic Diseases; Mice; Nerve Growth Factors; Obesity
PubMed: 35135706
DOI: 10.1016/j.tem.2022.01.001 -
International Journal of Molecular... Feb 2021Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world,... (Review)
Review
Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a for the diagnosis of both MDD and PTSD.
Topics: Animals; Biomarkers; Brain; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Humans; Nerve Growth Factors; Neurosteroids; Pregnanolone; Stress Disorders, Post-Traumatic
PubMed: 33578758
DOI: 10.3390/ijms22041758