Showing papers in "Frontiers in Molecular Neuroscience in 2019"

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.

Abstract: TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits as inclusion bodies in the brain and spinal cord of the patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While majority of the ALS cases (90-95%) are sporadic (sALS), among the familial ALS cases 5-10% involve the inheritance of mutations in the TARDBP gene and the remaining (90-95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS, and NEK1 etc. Strikingly however, majority of the sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unravelling the molecular mechanisms of the TDP-43 pathology, seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43’s pathology in ALS. We discuss the roles of TDP-43’s mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43’s amyloid-like in vitro aggregation, its physiological versus pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies towards TDP-43 disaggregation and ALS therapeutics.

Cannabinoid ligands targeting TRP channels

Abstract: Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be "ionotropic cannabinoid receptors." Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, N-arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ9-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.

Targeting Alpha-Synuclein as a Therapy for Parkinson's Disease.

Abstract: Parkinson's disease (PD) is one of the most common neurodegenerative disorders with a global burden of approximately 6.1 million patients. Alpha-synuclein has been linked to both the sporadic and familial forms of the disease. Moreover, alpha-synuclein is present in Lewy-bodies, the neuropathological hallmark of PD, and the protein and its aggregation have been widely linked to neurotoxic pathways that ultimately lead to neurodegeneration. Such pathways include autophagy/lysosomal dysregulation, synaptic dysfunction, mitochondrial disruption, and endoplasmic reticulum (ER) and oxidative stress. Alpha-synuclein has not only been shown to alter cellular pathways but also to spread between cells, causing aggregation in host cells. Therapeutic approaches will need to address several, if not all, of these angles of alpha-synuclein toxicity. Here we review the current advances in therapeutic efforts for PD that aim to produce a disease-modifying therapy by targeting the spread, production, aggregation, and degradation of alpha-synuclein. These include: receptor blocking strategies whereby putative alpha-synuclein receptors could be blocked inhibiting alpha-synuclein spread, an alpha-synuclein reduction which will decrease the amount alpha-synuclein available for aggregation and pathway disruption, the use of small molecules in order to target alpha-synuclein aggregation, immunotherapy and the increase of alpha-synuclein degradation by increasing autophagy/lysosomal flux. The research discussed here may lead to a disease-modifying therapy that tackles disease onset and progression in the future.

PKR: A Kinase to Remember

Abstract: Aging is a major risk factor for many diseases including metabolic syndrome, cancer, inflammation, and neurodegeneration. Identifying mechanistic common denominators underlying the impact of aging is essential for our fundamental understanding of age-related diseases and the possibility to propose new ways to fight them. One can define aging biochemically as prolonged metabolic stress, the innate cellular and molecular programs responding to it, and the new stable or unstable state of equilibrium between the two. A candidate to play a role in the process is protein kinase R (PKR), first identified as a cellular protector against viral infection and today known as a major regulator of central cellular processes including mRNA translation, transcriptional control, regulation of apoptosis, and cell proliferation. Prolonged imbalance in PKR activation is both affected by biochemical and metabolic parameters and affects them in turn to create a feedforward loop. Here, we portray the central role of PKR in transferring metabolic information and regulating cellular function with a focus on cancer, inflammation, and brain function. Later, we integrate information from open data sources and discuss current knowledge and gaps in the literature about the signaling cascades upstream and downstream of PKR in different cell types and function. Finally, we summarize current major points and biological means to manipulate PKR expression and/or activation and propose PKR as a therapeutic target to shift age/metabolic-dependent undesired steady states.

Neuroblastoma-A Neural Crest Derived Embryonal Malignancy.

Abstract: Neuroblastoma is a neural crest derived malignancy of the peripheral nervous system and is the most common and deadliest tumor of infancy. It is characterized by clinical heterogeneity with a disease spectrum ranging from spontaneous regression without any medical intervention to treatment resistant tumors with metastatic spread and poor patient survival. The events that lead to the development of neuroblastoma from the neural crest have not been fully elucidated. Here we discuss factors and processes within the neural crest that when dysregulated have the potential to be initiators or drivers of neuroblastoma development. A more precise biological understanding of neuroblastoma causes and cell of origin is highly warranted. This will give valuable information for the development of medicines that specifically target molecules within neuroblastoma cells and also give hint about the mechanisms behind treatment resistance that is frequently seen in neuroblastoma.

Role of Metabotropic Glutamate Receptors in Neurological Disorders.

Abstract: Glutamate is a fundamental excitatory neurotransmitter in the mammalian central nervous system (CNS), playing key roles in memory, neuronal development, and synaptic plasticity. Moreover, excessive glutamate release has been implicated in neuronal cell death. There are both ionotropic and metabotropic glutamate receptors (mGluRs), the latter of which can be divided into eight subtypes and three subgroups based on homology sequence and their effects on cell signaling. Indeed, mGluRs exert fine control over glutamate activity by stimulating several cell-signaling pathways via the activation of G protein-coupled (GPC) or G protein-independent cell signaling. The involvement of specific mGluRs in different forms of synaptic plasticity suggests that modulation of mGluRs may aid in the treatment of cognitive impairments related to several neurodevelopmental/psychiatric disorders and neurodegenerative diseases, which are associated with a high economic and social burden. Preclinical and clinical data have shown that, in the CNS, mGluRs are able to modulate presynaptic neurotransmission by fine-tuning neuronal firing and neurotransmitter release in a dynamic, activity-dependent manner. Current studies on drugs that target mGluRs have identified promising, innovative pharmacological tools for the treatment of neurodegenerative and neuropsychiatric conditions, including chronic pain.

Neuronal Cells Rearrangement During Aging and Neurodegenerative Disease: Metabolism, Oxidative Stress and Organelles Dynamic.

Abstract: Brain cells normally respond adaptively to oxidative stress or bioenergetic challenges, resulting from ongoing activity in neuronal circuits. During aging and in neurodegenerative disorders, these mechanisms are compromised. In fact, neurons show unique age-related changes in functions and metabolism, resulting in greater susceptibility to insults and disease. Aging affects the nervous system as well as other organs. More precisely, as the nervous system ages, neuron metabolism may change, inducing glucose hypometabolism, impaired transport of critical substrates underlying metabolism, alterations in calcium signaling, and mitochondrial dysfunction. Moreover, in neuronal aging, an accumulation of impaired and aggregated proteins in the cytoplasm and in mitochondria is observed, as the result of oxidative stress: reduced antioxidant defenses and/or increase of reactive oxygen species (ROS). These changes lead to greater vulnerability of neurons in various regions of the brain and increased susceptibility to several diseases. Specifically, the first part of the review article will focus on the major neuronal cells' rearrangements during aging in response to changes in metabolism and oxidative stress, while the second part will cover the neurodegenerative disease areas in detail.

Role of Exosomes in Central Nervous System Diseases

Abstract: There are many types of intercellular communication, and extracellular vesicles are one of the important forms of this. They are released by a variety of cell types, are heterogeneous, and can roughly be divided into microvesicles and exosomes according to their occurrence and function. Of course, exosomes do not just play a role in cell-to-cell communication. In the nervous system, exosomes can participate in intercellular communication, maintain the myelin sheath, and eliminate waste. Similarly, exosomes in the brain can play a role in central nervous system diseases, such as stroke, Alzheimer's disease (AD), Parkinson's disease (PD), prion disease, and traumatic encephalopathy (CTE), with both positive and negative effects (such as the transfer of misfolded proteins). Exosomes contain a variety of key bioactive substances and can therefore be considered as a snapshot of the intracellular environment. Studies have shown that exosomes from the central nervous system can be found in cerebrospinal fluid and peripheral body fluids, and that their contents will change with disease occurrence. Because exosomes can penetrate the blood brain barrier (BBB) and are highly stable in peripheral circulation, they can protect disease-related molecules well and therefore, using exosomes as a biomarker of central nervous system diseases is an attractive prospect as they can be used to monitor disease development and enable early diagnosis and treatment optimization. In this review, we discuss the current state of knowledge of exosomes, and introduce their pathophysiological roles in different diseases of the central nervous system as well as their roles and applications as a viable pathological biomarker.

Double-Edged Sword of Tumour Suppressor Genes in Schizophrenia.

Abstract: Schizophrenia (SCZ) is a common psychiatric disorder with polygenetic pathogenesis. Among the many identified candidate genes and loci, the group of tumour suppressor genes has drawn our interest. In this mini-review article, we describe evidence of a correlation between major tumour suppressor genes and SCZ development. Genetic mutations ranging from single nucleotide polymorphisms to large structural alterations have been found in tumour-related genes in patients with SCZ. Epigenetic mechanisms, including DNA methylation/acetylation and microRNA regulation of tumour suppressor genes, have also been implicated in SCZ. Beyond genetic correlations, we hope to establish causal relationships between tumour suppressor gene function and SCZ risk. Accumulating evidence shows that tumour suppressor genes may mediate cell survival and neural development, both of which contribute to SCZ aetiology. Moreover, converging intracellular signalling pathways indicate a role of tumour suppressor genes in SCZ pathogenesis. Tumour suppressor gene function may mediate a direct link between neural development and function and psychiatric disorders, including SCZ. A deeper understanding of how neural cell development is affected by tumour suppressors may lead to improved anti-psychotic drugs.

P2X7 Interactions and Signaling - Making Head or Tail of It

Abstract: Extracellular adenine nucleotides play important roles in cell-cell communication and tissue homeostasis. High concentrations of extracellular ATP released by dying cells are sensed as a danger signal by the P2X7 receptor, a non-specific cation channel. Studies in P2X7 knockout mice and numerous disease models have demonstrated an important role of this receptor in inflammatory processes. P2X7 activation has been shown to induce a variety of cellular responses that are not usually associated with ion channel function, for example changes in the plasma membrane composition and morphology, ectodomain shedding, activation of lipases, kinases, and transcription factors, as well as cytokine release and apoptosis. In contrast to all other P2X family members, the P2X7 receptor contains a long intracellular C-terminus that constitutes 40% of the whole protein and is considered essential for most of these effects. So far, over 50 different proteins have been identified to physically interact with the P2X7 receptor. However, few of these interactions have been confirmed in independent studies and for the majority of these proteins, the interaction domains and the physiological consequences of the interactions are only poorly described. Also, while the structure of the P2X7 extracellular domain has recently been resolved, information about the organization and structure of its C-terminal tail remains elusive. After shortly describing the structure and assembly of the P2X7 receptor, this review gives an update of the identified or proposed interaction domains within the P2X7 C-terminus, describes signaling pathways in which this receptor has been involved, and provides an overlook of the identified interaction partners.

Connexin Hemichannels in Astrocytes: Role in CNS Disorders.

Abstract: In the central nervous system (CNS), astrocytes form networks interconnected by gap junctions made from connexins of the subtypes Cx30 and Cx43. When unopposed by an adjoining hemichannel, astrocytic connexins can act as hemichannels to control the release of small molecules such as ATP and glutamate into the extracellular space. Accruing evidence indicates that astrocytic connexins are crucial for the coordination and maintenance of physiologic CNS activity. Here we provide an update on the role of astrocytic connexins in neurodegenerative disorders, glioma, and ischemia. In addition, we address the regulation of Cx43 in chronic pain.

The Role of Microglia and Astrocytes in Huntington's Disease.

Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain. Therefore, a better understanding of the neuroinflammatory environment in the brain in HD may lead to the development of targeted and innovative therapeutic opportunities.

MicroRNAs in Microglia: How do MicroRNAs Affect Activation, Inflammation, Polarization of Microglia and Mediate the Interaction Between Microglia and Glioma?

Abstract: The essential roles of microglia in maintaining homeostasis in the healthy brain and contributing to neuropathology are well documented. Emerging evidence suggests that epigenetic modulation regulates microglial behavior in both physiological and pathological conditions. MicroRNAs (miRNAs) are short, non-coding epigenetic regulators that repress target gene expression mostly via binding to 3’-untranslated region (3'-UTR) of mRNA in a Dicer-dependent manner. Dysregulation of certain miRNAs can contribute to microglial hyper-activation, persistent neuroinflammation, and abnormal macrophage polarization in the brain. These abnormal conditions can support the pathogenesis of neurological disorders such as glioma, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, ischemia, and spinal cord injury. However, the roles of miRNAs in microglia in health and neurological disease have not been systematically summarized. This review will firstly report the role of Dicer, a key endoribonulease that is responsible for most miRNA biogenesis in microglia. Secondly, we will focus on recent research about the function of miRNAs in activation, inflammation and polarization of microglia, respectively. In addition, potential crosstalk between microglia and glioma cells via miRNAs will be discussed in this part. Finally, the role of two essential miRNAs, miR-124, and miR-155, in microglia will be highlighted.

Schwann Cell Precursors; Multipotent Glial Cells in Embryonic Nerves.

Abstract: The cells of the neural crest, often referred to as neural crest stem cells, give rise to a number of sub-lineages, one of which is Schwann cells, the glial cells of peripheral nerves. Crest cells transform to adult Schwann cells through the generation of two well defined intermediate stages, the Schwann cell precursors (SCP) in early embryonic nerves, and immature Schwann cells (iSch) in late embryonic and perinatal nerves. Schwann cell precursors are formed when neural crest cells enter nascent nerves and form intimate relationships with axons, a diagnostic feature of glial cells. This involves large-scale changes in gene expression, including the activation of established glial cell markers. Like early glia in the CNS, radial glia, Schwann cell precursors retain developmental multipotency and contribute to other crest-derived lineages during embryonic development. Schwann cell precursors, closely related cells termed boundary cap cells, or later stages of the Schwann cell lineage have all been implicated as the tumour initiating cell in NF1 associated neurofibromas. Immature Schwann cells are formed from Schwann cell precursors in a process that involves the appearance of additional differentiation markers, autocrine survival circuits, cellular elongation, formation of endoneurial connective tissue and basal lamina. Finally, in peri-and post-natal nerves, immature Schwann cells are reversibly induced by axon-associated signals to form the myelin and non-myelin Schwann cells of adult nerves. This article discusses these events in detail, and describes the large number of molecular signalling systems that control glial development in embryonic nerves.

Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis.

Abstract: The discovery that prion protein can misfold into a pathological conformation that encodes structural information capable of both propagation and inducing severe neuropathology has revolutionized our understanding of neurodegenerative disease. Many neurodegenerative diseases with a protein misfolding component are now classified as "prion-like" owing to the propagation of both symptoms and protein aggregation pathology in affected individuals. The neuromuscular disorder amyotrophic lateral sclerosis (ALS) is characterized by protein inclusions formed by either TAR DNA-binding protein of 43 kDa (TDP-43), Cu/Zn superoxide dismutase (SOD1), or fused in sarcoma (FUS), in both upper and lower motor neurons. Evidence from in vitro, cell culture, and in vivo studies has provided strong evidence to support the involvement of a prion-like mechanism in ALS. In this article, we review the evidence suggesting that prion-like propagation of protein aggregation is a primary pathomechanism in ALS, focusing on the key proteins and genes involved in disease (TDP-43, SOD1, FUS, and C9orf72). In each case, we discuss the evidence ranging from biophysical studies to in vivo examinations of prion-like spreading. We suggest that the idiopathic nature of ALS may stem from its prion-like nature and that elucidation of the specific propagating protein assemblies is paramount to developing effective therapies.

Gut Microbiota Differs Between Parkinson's Disease Patients and Healthy Controls in Northeast China.

Abstract: Background: There is accumulating evidence suggesting a connection between the gut and Parkinson's disease (PD). Gut microbiota may play an important role in the intestinal lesions in PD patients. Objective: This study aims to determine whether gut microbiota differs between PD patients and healthy controls in Northeast of China, and to identify the factors that influence the changes in the gut microbiota. Methods: We enrolled 51 PD patients and 48 healthy controls in this study. Microbial species in stool samples were determined through 16S-rRNA gene sequencing. Dietary intakes were collected from a subset of 42 patients and 23 controls using a food frequency questionnaire (FFQ). Gut microbiota species richness, diversity, differential abundance of individual taxa between PD patients and controls, and the relationship between the gut microbiota abundance and the dietary and clinical factors were analyzed. Results: PD patients showed decreased species richness, phylogenetic diversity, β- diversity, and altered relative abundance in several taxa compared to the controls. PD- associated clinical scores appeared to be the most influential factors that correlated with the abundance of a variety of taxa. The most consistent findings suggested by multiple analyses used in this study were the increase of Akkermansia and the decrease of Lactobacillus in PD patients in Northeast China. Conclusion: Gut microbiota significantly differed between a group of PD patients and healthy controls in Northeast China, with decreased species richness, phylogenetic diversity, β-diversity, and altered relative abundance in several taxa compared to the controls.

Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors.

Abstract: Chronic stress is a key risk factor for depression, and microglia have been implicated in the pathogenesis of the disease. Recent studies show that the Nod-like receptor protein 3 (NLRP3) inflammasome is expressed in microglia and may play a crucial role in depression. However, the mechanism of NLRP3 inflammasome activation in hippocampal microglia and its role in depressive-like behaviors remain poorly understood. In this study, rats were subjected to 6 h of restraint stress per day for 21 days to produce a model of stress-induced depression. Behavioral tests and serum corticosterone were used to assess the success of the model. Furthermore, HAPI cells were pretreated with dexamethasone (5 × 10-7 M) to assess stress-induced changes in microglial cells in culture. The microglial marker Iba-1, reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) and key components of the NLRP3 inflammasome and its downstream inflammatory effectors (IL-1β and IL-18) were measured. Chronic stress induced depressive-like behavior, increased serum corticosterone levels and produced hippocampal structural changes. Chronic stress and dexamethasone both increased Iba-1 expression and ROS formation and also elevated levels of NF-κB, NLRP3, cleaved caspase-1, IL-1β and IL-18. After use of the NF-κB inhibitor BAY 117082 and knocked out NLRP3 in vitro decreased ROS formation and the expression of Iba-1, NF-κB and NLRP3 as well as levels of cleaved caspase-1, IL-1β and IL-18. These findings suggest that activation of the glucocorticoid receptor-NF-κB-NLRP3 pathway in hippocampal microglia mediates chronic stress-induced hippocampal neuroinflammation and depression-like behavior.

NMDAR Hypofunction Animal Models of Schizophrenia

Abstract: The N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis has been proposed to help understand the etiology and pathophysiology of schizophrenia. This hypothesis was based on early observations that NMDAR antagonists could induce a full range of symptoms of schizophrenia in normal human subjects. Accumulating evidence in humans and animal studies points to NMDAR hypofunctionality as a convergence point for various symptoms of schizophrenia. Here we review animal models of NMDAR hypofunction generated by pharmacological and genetic approaches, and how they relate to the pathophysiology of schizophrenia. In addition, we discuss the limitations of animal models of NMDAR hypofunction and their potential utility for therapeutic applications.

Targeting Autophagy for the Treatment of Alzheimer's Disease: Challenges and Opportunities

Abstract: Alzheimer's disease (AD) is the most common type of dementia which characterized by a progressive loss of memory and cognitive function due to degeneration of synapses and axons. Currently, there is no cure for AD. Deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs) are two hallmark pathologic changes in the brains of Alzheimer's patients. Autophagy is the major mechanism in cells responsible for removing protein aggregates. Accumulation of immature autophagic vacuoles (AVs) in dystrophic neurites of Alzheimer patients' brains suggests that autophagy process is disrupted. Till now, it is far from clear what role autophagy plays in AD, a causative role, a protective role, or just a consequence of the disease process itself. To design more effective therapeutic strategies towards this devastating disorder, it is essential to understand the exact role of autophagy played during different stages of AD.

Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved.

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors.

Abstract: Pain is an essential protective mechanism meant to prevent tissue damages in organisms. On the other hand, chronic or persistent pain caused, for example, by inflammation or nerve injury is long lasting and responsible for long-term disability in patients. Therefore, chronic pain and its management represents a major public health problem. Hence, it is critical to better understand chronic pain molecular mechanisms to develop innovative and efficient drugs. Over the past decades, accumulating evidence has demonstrated a pivotal role of glutamate in pain sensation and transmission, supporting glutamate receptors as promising potential targets for pain relieving drug development. Glutamate is the most abundant excitatory neurotransmitter in the brain. Once released into the synapse, glutamate acts through ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels triggering fast excitatory neurotransmission, and metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors modulating synaptic transmission. Eight mGluRs subtypes have been identified and are divided into three classes based on their sequence similarities and their pharmacological and biochemical properties. Of note, all mGluR subtypes (except mGlu6 receptor) are expressed within the nociceptive pathways where they modulate pain transmission. This review will address the role of mGluRs in acute and persistent pain processing and emerging pharmacotherapies for pain management.

Monoamine Oxidases (MAOs) as Privileged Molecular Targets in Neuroscience: Research Literature Analysis.

Abstract: Background: Monoamine oxidases (MAOs) were discovered nearly a century ago. This article aims to analyze the research literature landscape associated with MAOs as privileged class of neuronal enzymes (neuroenzymes) with key functions in the processes of neurodegeneration, serving as important biological targets in neuroscience. With the accumulating publications on this topic, we aimed to evaluate the publication and citation performance of the contributors, reveal the popular research themes, and identify its historical roots. Methods: The electronic database of Web of Science (WoS) Core Collection was searched to identify publications related to MAOs, which were analyzed according to their publication year, authorship, institutions, countries/regions, journal title, WoS category, total citation count, and publication type. VOSviewer was utilized to visualize the citation patterns of the words appearing in the titles and abstracts, and author keywords. CRExplorer was utilized to identify seminal references cited by the MAO publications. Results: The literature analysis was based on 19,854 publications. Most of them were original articles (n = 15,148, 76.3%) and reviews (n = 2,039, 10.3%). The top five WoS categories of the analyzed MAO publications were Pharmacology/Pharmacy (n = 4,664, 23.5%), Neurosciences (n = 4,416, 22.2%), Psychiatry (n = 2,906, 14.6%), Biochemistry/Molecular Biology (n = 2,691, 13.6%), and Clinical Neurology (n = 1,754, 8.8%). The top 10 institutions are scattered in the United States, UK, France, Sweden, Canada, Israel, and Russia, while the top 10 countries/regions with the most intensive research on the field of MAOs are the United States, followed by European and Asian countries. More highly cited publications generally involved neurotransmitters, such as dopamine (DA), serotonin, and norepinephrine (NE), as well as the MAO-A inhibitors moclobemide and clorgyline, and the irreversible MAO-B inhibitors selegiline and rasagiline. Conclusion: Through decades of research, the literature has accumulated many publications investigating the therapeutic effects of MAO inhibitors (MAOIs) on various neurological conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), and depression. We envision that MAO literature will continue to grow steadily, with more new therapeutic candidates being tested for better management of neurological conditions, in particular, with the development of multi-target acting drugs against neurodegenerative diseases.

Phosphoinositides: Regulators of Nervous System Function in Health and Disease.

Abstract: Phosphoinositides, the seven phosphorylated derivatives of phosphatidylinositol have emerged as regulators of key sub-cellular processes such as membrane transport, cytoskeletal function and plasma membrane signaling in eukaryotic cells. All of these processes are also present in the cells that constitute the nervous system of animals and in this setting too, these are likely to tune key aspects of cell biology in relation to the unique structure and function of neurons. Phosphoinositides metabolism and function are mediated by enzymes and proteins that are conserved in evolution, and analysis of knockouts of these in animal models implicate this signaling system in neural function. Most recently, with the advent of human genome analysis, mutations in genes encoding components of the phosphoinositide signaling pathway have been implicated in human diseases although the cell biological basis of disease phenotypes in many cases remains unclear. In this review we evaluate existing evidence for the involvement of phosphoinositide signaling in human nervous system diseases and discuss ways of enhancing our understanding of the role of this pathway in the human nervous system's function in health and disease.

Structural Insights Into TDP-43 and Effects of Post-translational Modifications.

Abstract: Transactive response DNA binding protein (TDP-43) is a key player in neurodegenerative diseases. In this review, we have gathered and presented structural information on the different regions of TDP-43 with high resolution structures available. A thorough understanding of TDP-43 structure, effect of modifications, aggregation and sites of localization is necessary as we develop therapeutic strategies targeting TDP-43 for neurodegenerative diseases. We discuss how different domains as well as post-translational modification may influence TDP-43 overall structure, aggregation and droplet formation. The primary aim of the review is to utilize structural insights as we develop an understanding of the deleterious behavior of TDP-43 and highlight locations of established and proposed post-translation modifications. TDP-43 structure and effect on localization is paralleled by many RNA-binding proteins and this review serves as an example of how structure may be modulated by numerous compounding elements.

Schwann Cell Precursors Generate the Majority of Chromaffin Cells in Zuckerkandl Organ and Some Sympathetic Neurons in Paraganglia.

Abstract: In humans, neurosecretory chromaffin cells control a number of important bodily functions, including those related to stress response. Chromaffin cells appear as a distinct cell type at the beginning of midgestation and are the main cellular source of adrenalin and noradrenalin released into the blood stream. In mammals, two different chromaffin organs emerge at a close distance to each other, the adrenal gland and Zuckerkandl organ (ZO). These two structures are found in close proximity to the kidneys and dorsal aorta, in a region where paraganglioma, pheochromocytoma and neuroblastoma originate in the majority of clinical cases. Recent studies showed that the chromaffin cells comprising the adrenal medulla are largely derived from nerve-associated multipotent Schwann cell precursors (SCPs) arriving at the adrenal anlage with the preganglionic nerve fibers, whereas the migratory neural crest cells provide only minor contribution. However, the embryonic origin of the ZO, which differs from the adrenal medulla in a number of aspects, has not been studied in detail. The ZO is composed of chromaffin cells in direct contact with the dorsal aorta and the intraperitoneal cavity and disappears through an autophagy-mediated mechanism after birth. In contrast, the adrenal medulla remains throughout the entire life and furthermore, is covered by the adrenal cortex. Using a combination of lineage tracing strategies with nerve- and cell type-specific ablations, we reveal that the ZO is largely SCP-derived and forms in synchrony with progressively increasing innervation. Moreover, the ZO develops hand-in-hand with the adjacent sympathetic ganglia that coalesce around the dorsal aorta. Finally, we were able to provide evidence for a SCP-contribution to a small but significant proportion of sympathetic neurons of the posterior paraganglia. Thus, this cellular source complements the neural crest, which acts as a main source of sympathetic neurons. Our discovery of a nerve-dependent origin of chromaffin cells and some sympathoblasts may help to understand the origin of pheochromocytoma, paraganglioma and neuroblastoma, all of which are currently thought to be derived from the neural crest or committed sympathoadrenal precursors.

Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors.

Abstract: α5 subunit containing GABA type A receptors (GABAARs) have long been an enigmatic receptor subtype of interest due to their specific brain distribution, unusual surface localization and key role in synaptic plasticity, cognition and memory. These receptors are uniquely positioned to sculpt both the developing and mature hippocampal circuitry due to high overall expression and a distinct peak within the critical synapse formation period during the second postnatal week. Unlike the majority of other GABAARs, they exhibit both receptor clustering at extrasynaptic sites via interactions with the radixin scaffold as well as synaptic sites via gephyrin, thus contributing respectively to tonic currents and synaptic GABAergic neurotransmission. α5 GABAAR signaling can be altered in neurodevelopmental disorders including autism and mental retardation and by inflammation in CNS injury and disease. Due to the unique physiology and pharmacology of α5 GABAARs, drugs targeting these receptors are being developed and tested as treatments for neurodevelopmental disorders, depression, schizophrenia, and mild cognitive impairment. This review article focuses on advances in understanding how the α5 subunit contributes to GABAAR neurobiology. In particular, I discuss both recent insights and remaining knowledge gaps for the functional role of these receptors, pathologies associated with α5 GABAAR dysfunction, and the effects and potential therapeutic uses of α5 receptor subtype targeted drugs.

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

Abstract: Many postsynaptic proteins undergo palmitoylation, the reversible attachment of the fatty acid palmitate to cysteine residues, which influences trafficking, localization, and protein interaction dynamics. Both palmitoylation by palmitoyl acyl transferases (PAT) and depalmitoylation by palmitoyl-protein thioesterases (PPT) is regulated in an activity-dependent, localized fashion. Recently, palmitoylation has received attention for its pivotal contribution to various forms of synaptic plasticity, the dynamic modulation of synaptic strength in response to neuronal activity. For instance, palmitoylation and depalmitoylation of the central postsynaptic scaffold protein postsynaptic density-95 (PSD-95) is important for synaptic plasticity. Here, we provide a comprehensive review of studies linking palmitoylation of postsynaptic proteins to synaptic plasticity.

Astrocyte, a Promising Target for Mood Disorder Interventions.

Abstract: Mood disorders have multiple phenotypes and complex underlying biological mechanisms and, as such, there are no effective therapeutic strategies. A review of recent work on the role of astrocytes in mood disorders is thus warranted, which we embark on here. We argue that there is tremendous potential for novel strategies for therapeutic interventions based on the role of astrocytes. Astrocytes are traditionally considered to have supporting roles within the brain, yet emerging evidence has shown that astrocytes have more direct roles in influencing brain function. Notably, evidence from postmortem human brain tissues has highlighted changes in glial cell morphology, density and astrocyte-related biomarkers and genes following mood disorders, indicating astrocyte involvement in mood disorders. Findings from animal models strongly imply that astrocytes not only change astrocyte morphology and physiological characteristics but also influence neural circuits via synapse structure and formation. This review pays particular attention to interactions between astrocytes and neurons and argues that astrocyte dysfunction affects the monoaminergic system, excitatory-inhibitory balance and neurotrophic states of local networks. Together, these studies provide a foundation of knowledge about the exact role of astrocytes in mood disorders. Importantly, we then change the focus from neurons to glial cells and the interactions between the two, so that we can understand newly proposed mechanisms underlying mood disorders, and to identify more diagnostic indicators or effective targets for treatment of these diseases.

Gut Inflammation in Association With Pathogenesis of Parkinson's Disease.

Abstract: Parkinson’s disease (PD) is a neurodegenerative disease that is generally thought to be caused by multiple factors, including environmental and genetic factors. Emerging evidence suggests that intestinal disturbances, such as constipation, are common non-motor symptoms of PD. Gut inflammation may be closely associated with pathogenesis in PD. This review aims to discuss the cross-talk between gut inflammation and PD pathology initiation and progression. Firstly, we will highlight the studies demonstrating how gut inflammation is related to PD. Secondly, we will analyze how gut inflammation spreads from the gastro-intestine to the brain. Here, we will mainly discuss the neural pathway of pathologic α-syn and the systemic inflammatory routes. Thereafter, we will address how alterations in the brain subsequently lead to dopaminergic neuron degeneration, in which oxidative stress, glutamate excitotoxicity, T cell driven inflammation and cyclooxygenase-2 (COX-2) are involved. We conclude a model of PD triggered by gut inflammation, which provides a new angle to understand the mechanisms of the disease.

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies.

Abstract: Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.