scholarly journals A home run for human NaCT/SLC13A5/INDY: cryo-EM structure and homology model to predict transport mechanisms, inhibitor interactions and mutational defects

2021 ◽  
Vol 478 (11) ◽  
pp. 2051-2057
Author(s):  
Valeria Jaramillo-Martinez ◽  
Vadivel Ganapathy ◽  
Ina L. Urbatsch
Keyword(s):  
3D Structure ◽  
Homology Model ◽  
Brain Dysfunction ◽  
Neurological Dysfunction ◽  
Metabolic Phenotype ◽  
Detailed Knowledge ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Function Relationship ◽  
The Brain

NaCT (SLC13A5) is a Na+-coupled transporter for citrate, which is expressed in the liver, brain, testes, and bone. It is the mammalian homolog of Drosophila INDY, a cation-independent transporter for citrate, whose partial loss extends lifespan in the organism. In humans, loss-of-function mutations in NaCT cause a disease with severe neurological dysfunction, characterized by neonatal epilepsy and delayed brain development. In contrast with humans, deletion of NaCT in mice results in a beneficial metabolic phenotype with protection against diet-induced obesity and metabolic syndrome; the brain dysfunction is not readily noticeable. The disease-causing mutations are located in different regions of human NaCT protein, suggesting that different mutations might have different mechanisms for the loss of function. The beneficial effects of NaCT loss in the liver versus the detrimental effects of NaCT loss in the brain provide an opportunity to design high-affinity inhibitors for the transporter that do not cross the blood-brain barrier so that only the beneficial effects could be harnessed. To realize these goals, we need a detailed knowledge of the 3D structure of human NaCT. The recent report by Sauer et al. in Nature describing the cryo-EM structure of human NaCT represents such a milestone, paving the way for a better understanding of the structure-function relationship for this interesting and clinically important transporter.

scholarly journals Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 669
Author(s):  
Valeria Jaramillo-Martinez ◽  
Sathish Sivaprakasam ◽  
Vadivel Ganapathy ◽  
Ina L. Urbatsch
Keyword(s):  
Caloric Restriction ◽  
Clinical Symptoms ◽  
Tissue Expression ◽  
Structural Features ◽  
Neurological Dysfunction ◽  
Metabolic Phenotype ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Relative Contribution ◽  
Partial Deficiency

INDY (I’m Not Dead Yet) is a plasma membrane transporter for citrate, first identified in Drosophila. Partial deficiency of INDY extends lifespan in this organism in a manner similar to that of caloric restriction. The mammalian counterpart (NaCT/SLC13A5) also transports citrate. In mice, it is the total, not partial, absence of the transporter that leads to a metabolic phenotype similar to that caloric restriction; however, there is evidence for subtle neurological dysfunction. Loss-of-function mutations in SLC13A5 (solute carrier gene family 13, member A5) occur in humans, causing a recessive disease, with severe clinical symptoms manifested by neonatal seizures and marked disruption in neurological development. Though both Drosophila INDY and mammalian INDY transport citrate, the translocation mechanism differs, the former being a dicarboxylate exchanger for the influx of citrate2− in exchange for other dicarboxylates, and the latter being a Na+-coupled uniporter for citrate2−. Their structures also differ as evident from only ~35% identity in amino acid sequence and from theoretically modeled 3D structures. The varied biological consequences of INDY deficiency across species, with the beneficial effects predominating in lower organisms and detrimental effects overwhelming in higher organisms, are probably reflective of species-specific differences in tissue expression and also in relative contribution of extracellular citrate to metabolic pathways in different tissues

scholarly journals Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease

2020 ◽  
Vol 117 (22) ◽  
pp. 12071-12079
Author(s):  
José M. López ◽  
Esther L. Outtrim ◽  
Rong Fu ◽  
Diane J. Sutcliffe ◽  
Rosa J. Torres ◽  
...  
Keyword(s):  
Uric Acid ◽  
Folic Acid ◽  
Biosynthetic Pathway ◽  
De Novo ◽  
Culture Media ◽  
Brain Dysfunction ◽  
Neurological Dysfunction ◽  
Purine Pathway ◽  
Hypoxanthine Guanine Phosphoribosyltransferase ◽  
The Brain

Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5′-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.

Training the brain: could it improve multiple sclerosis treatment?

2020 ◽  
Vol 31 (7) ◽  
pp. 779-792
Author(s):  
Berenice Anabel Silva ◽  
Esteban Alberto Miglietta ◽  
Carina Cintia Ferrari
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
Environmental Enrichment ◽  
Cognitive Stimulation ◽  
Loss Of Function ◽  
Pharmacological Treatments ◽  
Beneficial Effects ◽  
The Central Nervous System ◽  
The Brain ◽  
Multiple Sclerosis Treatment

AbstractMultiple sclerosis (MS) is a neurological disease characterized by neuroinflammation, demyelination and axonal degeneration along with loss of function in the central nervous system. For many years, research in MS has focused on the efficacy of pharmacological treatments. However, during the last years, many publications have been dedicated to the study of the efficacy of non-pharmacological strategies, such as physical exercise and cognitive training. Beneficial effects of the combination of both strategies on cognitive function have been described in both ageing adults and patients with neurodegenerative diseases, such as MS. The analysis of combining both physical and cognitive stimulation can be summarized by the environmental enrichment (EE) experiments, which are more suitable for animal models. EE refers to housing conditions consisting of exercise and cognitive and social stimulation. In this review, we will summarize the available studies that describe the influence of EE in both MS patients and MS animal models.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection

2019 ◽  
Vol 25 (23) ◽  
pp. 2555-2568 ◽  
Author(s):  
Rajeev Taliyan ◽  
Sarathlal K. Chandran ◽  
Violina Kakoty
Keyword(s):  
Diabetes Mellitus ◽  
Protein Trafficking ◽  
Metabolic Stress ◽  
Insulin Receptors ◽  
Metabolic Dysfunction ◽  
Beneficial Effects ◽  
Glucose And Lipid Metabolism ◽  
Endocrine Hormone ◽  
Metabolic Conditions ◽  
The Brain

Neurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.

The Effects of D-aspartate on Neurosteroids, Neurosteroid Receptors, and Inflammatory Mediators in Experimental Autoimmune Encephalomyelitis

2019 ◽  
Vol 19 (3) ◽  
pp. 316-325
Author(s):  
Mahdi Goudarzvand ◽  
Yaser Panahi ◽  
Reza Yazdani ◽  
Hosein Miladi ◽  
Saeed Tahmasebi ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Mediators ◽  
Mouse Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Oral Gavage ◽  
Autoimmune Encephalomyelitis ◽  
Beneficial Effects ◽  
17Β Estradiol ◽  
The Brain ◽  
Experimental Autoimmune

Objective: Experimental autoimmune encephalomyelitis (EAE) is a widely used model for multiple sclerosis. The present study has been designed to compare the efficiencies of oral and intraperitoneal (IP) administration of D-aspartate (D-Asp) on the onset and severity of EAE, the production of neurosteroids, and the expression of neurosteroid receptors and inflammatory mediators in the brain of EAE mice. Methods: In this study, EAE was induced in C57BL/6 mice treated with D-Asp orally (D-Asp-Oral) or by IP injection (D-Asp-IP). On the 20th day, brains (cerebrums) and cerebellums of mice were evaluated by histological analyses. The brains of mice were analyzed for: 1) Neurosteroid (Progesterone, Testosterone, 17β-estradiol) concentrations; 2) gene expressions of cytokines and neurosteroid receptors by reverse transcription polymerase chain reaction, and 3) quantitative determination of D-Asp using liquid chromatography-tandem mass spectrometry. Further, some inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) were identified in the mouse serum using enzyme-linked immunosorbent assay kits. Results: Our findings demonstrated that after D-Asp was administered, it was taken up and accumulated within the brain. Further, IP injection of D-Asp had more beneficial effects on EAE severity than oral gavage. The concentration of the testosterone and 17β-estradiol in D-Asp-IP group was significantly higher than that of the control group. There were no significant differences in the gene expression of cytokine and neurosteroid receptors between control, D-Asp-IP, and D-Asp-Oral groups. However, IP treatment with D-Asp significantly reduced C-C motif chemokine ligand 2 and MMP-2 serum levels compared to control mice. Conclusion: IP injection of D-Asp had more beneficial effects on EAE severity, neurosteroid induction and reduction of inflammatory mediators than oral gavage.

Boswellia serrata Oleo-Gum-Resin and its Effect on Memory Functions: A Review

2020 ◽  
Vol 10 (4) ◽  
pp. 355-363
Author(s):  
Mohaddese Mahboubi ◽  
Leila Mohammad Taghizadeh Kashani
Keyword(s):  
Memory Loss ◽  
Modern Medicine ◽  
Waste Materials ◽  
Boswellia Serrata ◽  
Memory Functions ◽  
Beneficial Effects ◽  
Waste Production ◽  
Nursing Mothers ◽  
Traditional Practitioners ◽  
The Brain

Background: In Iranian Traditional Medicine, Boswellia serrata oleo-gum resins were used for the treatment of "Nisyan". "Nisyan" was equivalent to a reduction of memory or forgetfulness. Objective: This review evaluates the traditional believes of B. serrata and memory and its effectiveness on memory loss. Methods: We extracted all traditional and modern information on B. serrata oleo-gum resin preparations and memory from scientific accessible resources (Google Scholar, PubMed, Springer, Science direct, Wiley), non-accessible resources and traditional books. Results: In traditional manuscripts, "Nisyan" is equal to memory loss in modern medicine and was believed to happen as the result of pouring the waste materials into the brain. Traditional practitioners treated "Nisyan" by inhibition of waste production in the brain or cleaning the brain from waste materials. They recommended using the plants with warming effects on the brain. It was believed that B. serrata had beneficial effects on memory functions and its memory enhancing effects have been the subject of pharmacological and clinical trial studies. Conclusion: Despite some documents on the effectiveness of B. serrata oleo-gum-resin on memory functions, there is gap between these investigations, especially in pregnant and nursing mothers. More investigations with large clinical trials are required to complete flaw in order to improve the therapeutic applications of B. serrata on memory functions.

Huntington Disease

2019 ◽  
pp. 644-678
Author(s):  
Jane S. Paulsen
Keyword(s):  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Behavioral Control ◽  
Time Estimation ◽  
Brain Dysfunction ◽  
Medium Spiny Neuron ◽  
Loss Of Function ◽  
Neuron Death ◽  
Gene Therapies ◽  
Underlying Mechanisms

Huntington disease (HD) is a autosomal dominant neurodegenerative disease caused by expansion of a trinucleotide repeat (cytosine, adenine, and guanine [CAG]) on the short arm of chromosome four. Average age of motor diagnosis is 39 years, and age at diagnosis is associated with the length of the CAG mutation. The prodrome of HD can be recognized 15 years prior to motor diagnosis and is characterized by subtle impairments in emotional recognition, smell identification, speed of processing, time estimation and production, and psychiatric abnormalities. HD shows particular vulnerability of the medium spiny neuron in the basal ganglia. Progressive brain dysfunction and neuron death lead to insidious loss of function in motor, cognitive, and behavioral control over 34 years (17 prodromal and 17 post-diagnosis). Treatment plans rely on genetic counseling, psychiatric symptom treatment as needed, physical therapy, and environmental modifications. There are two treatments for the reduction of chorea, but there are no disease-modifying therapies. Experimental therapeutics are rapidly emerging with multiple and various targets, however, and gene therapies to silence the mutant HD gene are currently ongoing. This chapter reviews clinical and neuropathological descriptions of HD and discusses potential underlying mechanisms and animal models, diagnostic and clinical assessments used to characterize and track the disease, treatment planning, and challenges for research to advance care.

scholarly journals Brain mast cells link the immune system to anxiety-like behavior

2008 ◽  
Vol 105 (46) ◽  
pp. 18053-18057 ◽  
Author(s):  
Katherine M. Nautiyal ◽  
Ana C. Ribeiro ◽  
Donald W. Pfaff ◽  
Rae Silver
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Neural Systems ◽  
Loss Of Function ◽  
Littermate Control ◽  
Cytokines And Chemokines ◽  
Function Models ◽  
The Brain

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient KitW−sh/W−sh (sash−/−) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

scholarly journals SARS-CoV-2: is there neuroinvasion?

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Conor McQuaid ◽  
Molly Brady ◽  
Rashid Deane
Keyword(s):  
Respiratory Distress ◽  
Vascular Dysfunction ◽  
Multiorgan Failure ◽  
Neurological Complications ◽  
Wide Distribution ◽  
The Body ◽  
Health Conditions ◽  
Main Body ◽  
Beneficial Effects ◽  
The Brain

Abstract Background SARS-CoV-2, a coronavirus (CoV), is known to cause acute respiratory distress syndrome, and a number of non-respiratory complications, particularly in older male patients with prior health conditions, such as obesity, diabetes and hypertension. These prior health conditions are associated with vascular dysfunction, and the CoV disease 2019 (COVID-19) complications include multiorgan failure and neurological problems. While the main route of entry into the body is inhalation, this virus has been found in many tissues, including the choroid plexus and meningeal vessels, and in neurons and CSF. Main body We reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions (obesity, hypertension and diabetes), neurological COVID-19 manifestation and the aging cerebrovascualture. The overall aim is to provide the general reader with a breadth of information on this type of virus and the wide distribution of its main receptor so as to better understand the significance of neurological complications, uniqueness of the brain, and the pre-existing medical conditions that affect brain. The main issue is that there is no sound evidence for large flux of SARS-CoV-2 into brain, at present, compared to its invasion of the inhalation pathways. Conclusions While SARS-CoV-2 is detected in brains from severely infected patients, it is unclear on how it gets there. There is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus. The consensus, based on the normal route of infection and presence of SARS-CoV-2 in severely infected patients, is that the olfactory mucosa is a possible route into brain. Studies are needed to demonstrate flux of SARS-CoV-2 into brain, and its replication in the parenchyma to demonstrate neuroinvasion. It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure. Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.

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