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1.
Semin Cell Dev Biol ; 112: 92-104, 2021 04.
Article in English | MEDLINE | ID: mdl-33323321

ABSTRACT

Building evidence reveals the importance of maintaining lipid homeostasis for the health and function of neurons, and upper motor neurons (UMNs) are no exception. UMNs are critically important for the initiation and modulation of voluntary movement as they are responsible for conveying cerebral cortex' input to spinal cord targets. To maintain their unique cytoarchitecture with a prominent apical dendrite and a very long axon, UMNs require a stable cell membrane, a lipid bilayer. Lipids can act as building blocks for many biomolecules, and they also contribute to the production of energy. Therefore, UMNs require sustained control over the production, utilization and homeostasis of lipids. Perturbations of lipid homeostasis lead to UMN vulnerability and progressive degeneration in diseases such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Here, we discuss the importance of lipids, especially for UMNs.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Lipid Metabolism/genetics , Motor Neuron Disease/metabolism , Motor Neurons/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Axons/metabolism , Axons/pathology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Dendrites/genetics , Dendrites/metabolism , Dendrites/pathology , Humans , Lipids/genetics , Motor Neuron Disease/genetics , Motor Neuron Disease/pathology , Motor Neurons/pathology , Spinal Cord/metabolism , Spinal Cord/pathology
2.
Neurobiol Dis ; 178: 106022, 2023 03.
Article in English | MEDLINE | ID: mdl-36716828

ABSTRACT

Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a significant reduction in astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.


Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Mice , Animals , Amyotrophic Lateral Sclerosis/metabolism , Motor Neurons/pathology , Mitochondria/pathology , DNA-Binding Proteins/metabolism
3.
Int J Mol Sci ; 21(18)2020 Sep 18.
Article in English | MEDLINE | ID: mdl-32962107

ABSTRACT

Extracellular vesicles (EVs) have recently attracted a great deal of interest as they may represent a new biosignaling paradigm. According to the mode of biogenesis, size and composition, two broad categories of EVs have been described, exosomes and microvesicles. EVs have been shown to carry cargoes of signaling proteins, RNA species, DNA and lipids. Once released, their content is selectively taken up by near or distant target cells, influencing their behavior. Exosomes are involved in cell-cell communication in a wide range of embryonic developmental processes and in fetal-maternal communication. In the present review, an outline of the role of EVs in neural development, regeneration and diseases is presented. EVs can act as regulators of normal homeostasis, but they can also promote either neuroinflammation/degeneration or tissue repair in pathological conditions, depending on their content. Since EV molecular cargo constitutes a representation of the origin cell status, EVs can be exploited in the diagnosis of several diseases. Due to their capability to cross the blood-brain barrier (BBB), EVs not only have been suggested for the diagnosis of central nervous system disorders by means of minimally invasive procedures, i.e., "liquid biopsies", but they are also considered attractive tools for targeted drug delivery across the BBB. From the therapeutic perspective, mesenchymal stem cells (MSCs) represent one of the most promising sources of EVs. In particular, the neuroprotective properties of MSCs derived from the dental pulp are here discussed.


Subject(s)
Axons/metabolism , Cell-Derived Microparticles/metabolism , Exosomes/metabolism , Nervous System Diseases/metabolism , Neural Stem Cells/metabolism , Amyotrophic Lateral Sclerosis/metabolism , Blood-Brain Barrier/metabolism , Cell Communication , Dental Pulp/cytology , Dental Pulp/metabolism , Female , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Nervous System Diseases/diagnosis , Nervous System Diseases/prevention & control , Neural Stem Cells/cytology , Placenta/metabolism , Pregnancy , Regeneration/genetics
4.
J Neuroinflammation ; 16(1): 196, 2019 Oct 30.
Article in English | MEDLINE | ID: mdl-31666087

ABSTRACT

BACKGROUND: The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies. METHODS: We investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43A315T-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest. RESULTS: We detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased. CONCLUSIONS: There is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , DNA-Binding Proteins/metabolism , Motor Cortex/metabolism , Motor Cortex/pathology , Receptors, CCR2/metabolism , Adult , Aged , Animals , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged
5.
Acta Neuropathol ; 137(1): 47-69, 2019 01.
Article in English | MEDLINE | ID: mdl-30450515

ABSTRACT

Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as "TDP-43 pathology" in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.


Subject(s)
DNA-Binding Proteins/metabolism , Endoplasmic Reticulum/metabolism , Mitochondria/metabolism , Nuclear Envelope/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Humans , Mice, Transgenic , Mitochondria/pathology , Motor Neurons/pathology
6.
Hum Mol Genet ; 25(6): 1074-87, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26755825

ABSTRACT

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated Alsin(KO)-UeGFP mice, by crossing Alsin(KO) and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.


Subject(s)
Guanine Nucleotide Exchange Factors/deficiency , Motor Neurons/metabolism , Pyramidal Tracts/pathology , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Autophagy/physiology , Axons/pathology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Dendrites/metabolism , Disease Models, Animal , Female , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Mice , Mice, Knockout , Motor Neuron Disease/genetics , Motor Neuron Disease/metabolism , Motor Neuron Disease/pathology , Motor Neurons/pathology , Mutation , Pyramidal Tracts/metabolism , Spastic Paraplegia, Hereditary/genetics , Spastic Paraplegia, Hereditary/metabolism , Spastic Paraplegia, Hereditary/pathology
7.
Cell Tissue Res ; 368(2): 389-396, 2017 05.
Article in English | MEDLINE | ID: mdl-27139181

ABSTRACT

In response to various hormonal (follicle-stimulating hormone [FSH] and testosterone [T]) and biochemical inputs, testicular Sertoli cells (Sc) produce factors that regulate spermatogenesis. A number of FSH- and T-responsive Sc-specific genes, necessary for spermatogenesis, have been identified to date. However, the hormone-induced in vitro expression pattern of most of these genes is reported to be inconsistent at various time points in primary rat Sc cultures. As a matter of convenience, cultured Sc are constantly exposed to hormones for a few hours to days in the reported literature, although Sc are exposed to pulsatile FSH and T in vivo. The major aim of the present study is to evaluate the advantage, if any, of the in vitro administration of pulsatile hormone (FSH and T in combination) treatment on gene expression of cultured Sc as compared with that of constant hormone treatment. Pulsatile treatment (a 30-min hormonal exposure every 3 h) mimicking the in vivo condition reveals a more prominent effect of hormones in augmenting gene expression as compared with constant treatment. Our results indicate that the expressions of Stem cell factor (Scf, only responsive to FSH), Claudin11 (only responsive to T) and Transferrin (both FSH- and T-responsive) mRNAs are significantly higher at 12 h upon pulsatile treatment than upon constant hormonal treatment. Maximal expression of relevant genes because of pulsatile treatment with hormones suggests that this protocol provides a more suitable premise for assessing hormone-induced gene expression in isolated Sc than one involving constant exposure to hormones.


Subject(s)
Sertoli Cells/metabolism , Animals , Cells, Cultured , Claudins/genetics , Claudins/metabolism , Follicle Stimulating Hormone/pharmacology , Gene Expression Regulation/drug effects , Male , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Wistar , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Receptors, FSH/genetics , Receptors, FSH/metabolism , Sertoli Cells/drug effects , Stem Cell Factor/genetics , Stem Cell Factor/metabolism , Testosterone/pharmacology , Transferrin/genetics , Transferrin/metabolism
8.
J Plant Res ; 129(3): 463-76, 2016 May.
Article in English | MEDLINE | ID: mdl-26915037

ABSTRACT

Decomposition, nutrient, and isotopic (δ(13)C and δ(15)N) dynamics during 1 year were studied for leaf and twig litters of Pinus densiflora, Castanea crenata, Erigeron annuus, and Miscanthus sinensis growing on a highly weathered soil with constrained nutrient supply using litterbags in a cool temperate region of South Korea. Decay constant (k/year) ranged from 0.58 to 1.29/year, and mass loss ranged from 22.36 to 58.43 % among litter types. The results demonstrate that mass loss and nutrient dynamics of decomposing litter were influenced by the seasonality of mineralization and immobilization processes. In general, most nutrients exhibited alternate phases of rapid mineralization followed by gradual immobilization, except K, which was released throughout the field incubation. At the end of study, among all the nutrients only N and P showed net immobilization. Mobility of different nutrients from decomposing litter as the percentage of initial litter nutrient concentration was in the order of K > Mg > Ca > N ≈ P. The δ(13)C (0.32-6.70 ‰) and δ(15)N (0.74-3.90 ‰) values of residual litters showed nonlinear increase and decrease, respectively compared to initial isotopic values during decomposition. Litter of different functional types and chemical quality converged toward a conservative nutrient use strategy through mechanisms of slow decomposition and slow nutrient mobilization. Our results indicate that litter quality and season, are the most important regulators of litter decomposition in these forests. The results revealed significant relationships between litter decomposition rates and N, C:N ratio and P, and seasonality (temperature). These results and the convergence of different litters towards conservative nutrient use in these nutrient constrained ecosystems imply optimization of litter management because litter removal can have cascading effects on litter decomposition and nutrient availability in these systems.


Subject(s)
Carbon/metabolism , Nitrogen/metabolism , Plant Leaves/metabolism , Plants/metabolism , Biomass , Carbon Isotopes , Geography , Nitrogen Isotopes , Seasons
9.
Chemosphere ; 317: 137895, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36657573

ABSTRACT

Successful application and accurate interpretation of strontium (Sr) isotope ratios (87Sr/86Sr) requires underlying information about the large-scale variabilities in their signatures from a variety of environmental samples, which can be correlated with the Sr isotopic signatures of underlying local geology. In this national-scale study, we analyzed 87Sr/86Sr in soil, plants, stream water, and Chinese mystery snail (Cipangopaludina chinensis) shells collected from South Korea to evaluate large-scale spatial variabilities, interpret relationships among isotopic signatures of various sample types, and generate spatial distribution isoscapes reflecting the heterogeneity of isotopic signatures across South Korea. Non-parametric comparisons among environmental samples showed non-significant differences in their isotopic ratios. The 87Sr/86Sr of plant and soil samples were strongly correlated (R2adj = 0.93), suggesting that both reflect national-scale lithological properties. Similarly, the 87Sr/86Sr of shells showed strong correlations with the 87Sr/86Sr of both plant and soil samples (R2adj = 0.90). The 87Sr/86Sr signatures of environmental samples in this study aligned with expected Sr isotopic values and generally reflected local geology. Spatial distribution maps of samples showed similar 87Sr/86Sr spatial patterns, with high radiogenic values from granitic and granitic gneiss rocks systems and low radiogenic values from volcanic and sedimentary rock systems. Stream water samples showed significant correlations with soil and plant isotopic ratios, but with a low coefficient of determination (R2adj = 0.68). The deviations were much larger for samples with 87Sr/86Sr > 0.720. Further study is needed to improve the accuracy of baseline determination and interpretation of stream water isotopic variations.


Subject(s)
Soil , Strontium Isotopes , Strontium Isotopes/analysis , Water , Republic of Korea , Rivers , Strontium
10.
Am J Physiol Endocrinol Metab ; 303(7): E886-98, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22850685

ABSTRACT

FSH and Testosterone (T) regulate spermatogenesis via testicular Sertoli cells (Sc), which bear receptors for these hormones. Despite sufficient circulating levels of FSH and T postnatally, predominant appearance of spermatogonia B and spermatocytes is not discernible until 11 and 18 days of postnatal age, respectively, in rat testes. In an attempt to explore the underlying causes, we cultured Sc from neonatal (5- and 9-day-old) and prepubertal (12- and 19-day-old) rat testes and compared the status of FSH receptor (FSH-R) and androgen receptor (AR) signaling. Protein and mRNA levels of FSH-R and AR remained uniform in cultured Sc from all age groups. Androgen binding ability of AR was similar, and T-induced nuclear localization of AR was discernible in Sc from all age groups. Binding of FSH to FSH-R, subsequent production of cAMP, and mRNA of stem cell factor (SCF) and glial cell line-derived neurotrophic factor (GDNF), known to be essential for the robust differentiation of repopulating spermatogonia, were significantly augmented in prepubertal Sc compared with those in neonatal Sc. However, treatment of neonatal Sc with cholera toxin or forskolin, which stimulate cAMP production bypassing FSH-R, demonstrated a concomitant rise in SCF and GDNF mRNA expression, which was similar to the FSH-mediated rise observed in prepubertal Sc. These observations suggested that, during prepubertal Sc maturation, the ability of FSH-R to respond to FSH is significantly augmented and is associated with the robust differentiation of repopulating spermatogonia, and such a switch in Sc from FSH-resistant to FSH-responsive mode during prepubertal development may underlie the initiation of robust spermatogenesis.


Subject(s)
Follicle Stimulating Hormone/physiology , Receptors, FSH/metabolism , Sertoli Cells/physiology , Spermatogenesis/physiology , Testis/growth & development , Testis/physiology , Animals , Animals, Newborn , Cells, Cultured , Cholera Toxin/pharmacology , Colforsin/pharmacology , Cyclic AMP/biosynthesis , Follicle Stimulating Hormone/blood , Glial Cell Line-Derived Neurotrophic Factor/biosynthesis , Male , Rats , Rats, Wistar , Receptors, Androgen/analysis , Receptors, FSH/analysis , Sertoli Cells/drug effects , Spermatogenesis/drug effects , Stem Cell Factor/biosynthesis , Testis/drug effects , Testosterone/blood
11.
Biosci Biotechnol Biochem ; 76(11): 2096-100, 2012.
Article in English | MEDLINE | ID: mdl-23132585

ABSTRACT

An elemental analysis was performed on 30 Korean and Chinese kimchi samples in combination with strontium (Sr) isotope ratio measurements to develop a method for tracing the geographic origins of Korean and Chinese kimchi. We found a distinct difference between Korean and Chinese kimchi in such specific elements as K, Na, Ca, Ba, Sr, Zn, Li, and Sc, but no significant difference in the Sr isotope ratio. A comparative analysis was performed with washed kimchi (containing no submaterial) and unwashed kimchi to evaluate the effect of submaterials on the determination of geographic origin. A linear discriminant analysis provided a clear distinction between Korean and Chinese kimchi. The results indicate that combining multi-elemental and statistical analyses has the potential to determine the geographic origins of such processed food as kimchi.


Subject(s)
Food Analysis , Food Handling , Vegetables/chemistry , China , Discriminant Analysis , Korea , Principal Component Analysis , Strontium Isotopes/analysis
12.
Sci Rep ; 12(1): 4287, 2022 03 11.
Article in English | MEDLINE | ID: mdl-35277554

ABSTRACT

Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected in upper motor neurons (UMNs) with TDP-43 pathology, a pathology that is predominantly present in both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). While same mitochondrial problems are present in the UMNs of ALS patients with TDP-43 pathology and UMNs of TDP-43 mouse models, and since pathologies are shared at a cellular level, regardless of species, we first analyzed the metabolite profile of both healthy and diseased motor cortex to investigate whether metabolomic changes occur with respect to TDP-43 pathology. High-performance liquid chromatography, high-resolution mass spectrometry and tandem mass spectrometry (HPLC-MS/MS) for metabolite profiling began to suggest that reduced levels of NAD+ is one of the underlying causes of metabolomic problems. Since nicotinamide mononucleotide (NMN) was reported to restore NAD+ levels, we next investigated whether NMN treatment would improve the health of diseased corticospinal motor neurons (CSMN, a.k.a. UMN in mice). prpTDP-43A315T-UeGFP mice, the CSMN reporter line with TDP-43 pathology, allowed cell-type specific responses of CSMN to NMN treatment to be assessed in vitro. Our results show that metabolomic defects occur early in ALS motor cortex and establishing NAD+ balance could offer therapeutic benefit to UMNs with TDP-43 pathology.


Subject(s)
Amyotrophic Lateral Sclerosis , Motor Cortex , Amyotrophic Lateral Sclerosis/metabolism , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Mice , Mice, Transgenic , Motor Cortex/metabolism , NAD/metabolism , Tandem Mass Spectrometry
13.
Sci Rep ; 12(1): 5383, 2022 03 30.
Article in English | MEDLINE | ID: mdl-35354901

ABSTRACT

Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.


Subject(s)
Amyotrophic Lateral Sclerosis , Riluzole , Amyotrophic Lateral Sclerosis/drug therapy , Animals , Edaravone/pharmacology , Humans , Mice , Motor Neurons , Riluzole/pharmacology , Riluzole/therapeutic use , Superoxide Dismutase
14.
Sci Total Environ ; 806(Pt 3): 151352, 2022 Feb 01.
Article in English | MEDLINE | ID: mdl-34728202

ABSTRACT

Natural variations of 87Sr/86Sr ratios in biological samples, such as human hair, provide a biological record of provenance. Spatial distribution maps reflecting heterogeneity in isotopic signatures across large geographical regions are helpful for discerning the provenance and mobility of organisms. In this national-scale study conducted across South Korea, we investigated the spatial distribution patterns of 87Sr/86Sr ratios in human hair and tap water samples to determine their spatial variabilities and the relationships of isotopic signatures between hair and tap water. The strontium isoscapes of tap water and hair showed similar spatial distribution patterns. Non-parametric comparison indicated no significant differences in isotopic ratios between the two sample types. The 87Sr/86Sr ratios in human hair showed a significant and strong correlation with the ratios in tap water in eastern Korea, suggesting potential use of 87Sr/86Sr ratios in provenance studies. However, tap water and hair samples from western Korea did not show significant correlation between them, overall reducing the predictive power of the hair 87Sr/86Sr ratios for provenance studies. The deviation between 87Sr/86Srtap water and 87Sr/86Srhair was much larger in western coastal areas than in eastern Korea. Relatively high utilization of groundwater or exogenous materials, such as Asian dust, may have been responsible for this pattern. To fully utilize the potential of the strontium isotope signature as a biorecorder in provenance studies, it is essential to evaluate the effects of groundwater and other exogenous materials on the isotope signatures of hair and other biological samples. In this study, only hair samples from males were used to develop 87Sr/86Sr isoscapes. Therefore, further studies are required to examine the applicability of 87Sr/86Sr hair isoscapes based solely on human hair samples from males to forensic and provenance studies of human hair samples from females.


Subject(s)
Strontium Isotopes , Water , Female , Hair , Humans , Isotopes , Male , Strontium
15.
Metabolites ; 12(2)2022 Feb 12.
Article in English | MEDLINE | ID: mdl-35208248

ABSTRACT

Pathogenic variants in ALS2 have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with ALS2 mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options. There is an immense need to reveal the underlying causes of the disease and to identify potential biomarkers. To shed light onto the metabolomic events that are perturbed with respect to ALS2 mutations, we investigated the metabolites present in the serum and plasma of a three-year-old female patient (AO) harboring pathogenic variants in ALS2, together with her relatives, healthy male and female controls, as well as another two-year-old patient DH, who had mutations at different locations and domains of ALS2. Serum and plasma samples were analyzed with a quantitative metabolomic approach to reveal the identity of metabolites present in serum and plasma. This study not only shed light onto the perturbed cellular pathways, but also began to reveal the presence of a distinct set of key metabolites that are selectively present or absent with respect to ALS2 mutations, laying the foundation for utilizing metabolites as potential biomarkers for a subset of ALS.

16.
Brain Sci ; 11(6)2021 Jun 07.
Article in English | MEDLINE | ID: mdl-34200232

ABSTRACT

Corticospinal motor neurons (CSMN) are an indispensable neuron population for the motor neuron circuitry. They are excitatory projection neurons, which collect information from different regions of the brain and transmit it to spinal cord targets, initiating and controlling motor function. CSMN degeneration is pronounced cellular event in motor neurons diseases, such as amyotrophic lateral sclerosis (ALS). Genetic mutations contribute to only about ten percent of ALS. Thus understanding the involvement of other factors, such as epigenetic controls, is immensely valuable. Here, we investigated epigenomic signature of CSMN that become diseased due to misfolded SOD1 toxicity and TDP-43 pathology, by performing quantitative analysis of 5-methylcytosine (5mC) and 5-hydroxymethycytosine (5hmC) expression profiles during end-stage of the disease in hSOD1G93A, and prpTDP-43A315T mice. Our analysis revealed that expression of 5mC was specifically reduced in CSMN of both hSOD1G93A and prpTDP-43A315T mice. However, 5hmC expression was increased in the CSMN that becomes diseased due to misfolded SOD1 and decreased in CSMN that degenerates due to TDP-43 pathology. These results suggest the presence of a distinct difference between different underlying causes. These differential epigenetic events might modulate the expression profiles of select genes, and ultimately contribute to the different paths that lead to CSMN vulnerability in ALS.

17.
Clin Transl Med ; 11(2): e336, 2021 02.
Article in English | MEDLINE | ID: mdl-33634973

ABSTRACT

BACKGROUND: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies. METHODS: Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses. RESULTS: Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration. CONCLUSIONS: Mechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.


Subject(s)
Endoplasmic Reticulum/pathology , Mitochondria/pathology , Motor Neuron Disease/pathology , Proteostasis Deficiencies/pathology , Superoxide Dismutase-1/metabolism , TDP-43 Proteinopathies/pathology , Animals , Endoplasmic Reticulum/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Motor Neuron Disease/metabolism , Proteostasis Deficiencies/metabolism , Rotarod Performance Test , TDP-43 Proteinopathies/metabolism
18.
Sci Total Environ ; 749: 142352, 2020 Dec 20.
Article in English | MEDLINE | ID: mdl-33370907

ABSTRACT

Evaluating the decomposition-based change dynamics of various elements in plant litter is important for improving our understanding about their biogeochemical cycling in ecosystems. We have studied the concentrations of major, trace, and rare earth elements (REEs) (34 elements) in green tissue litter, and soil and their dynamics in the decomposing litters of successional annual fleabane (Erigeron annuus) and silvergrass (Miscanthus sinensis). Concentrations of major and trace elements in the litter of annual fleabane were 1.02-2.71 times higher compared to silvergrass. For REEs the difference between the two litter types for elements studied was in the range of 1.02-1.29 times. Both the litters showed a general decrease in the concentrations of elements in the initial stages of decomposition (60-90 days). All the major and trace elements (except for Na) in silvergrass showed a net increase in concentration at the end of the decomposition study (48.9-52.5% accumulated mass loss). Contrastingly, a few trace elements (Mn, Mo, Sr, Zn, Sb, and Cd) in annual fleabane showed a net decrease in their concentrations. For REEs, there was an increase in concentrations as well as in net amounts in both litter types. Similarities observed in the dynamics together with high and significant correlations among them likely suggest their common source. The higher concentrations of REEs in soil likely suggest its role in the net increase in REEs' concentrations and amount in litter during decomposition.


Subject(s)
Metals, Rare Earth , Trace Elements , Ecosystem , Metals, Rare Earth/analysis , Republic of Korea , Soil , Trace Elements/analysis
19.
Data Brief ; 30: 105666, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32426436

ABSTRACT

The data presented here include the results of oxygen (δ18O) and hydrogen (δ2H) isotope analyses of water and human scalp hair samples collected from throughout the South Korea. The purpose of data collection was to generate isoscapes of oxygen and hydrogen isotopes for South Korea. To achieve the objective, we collected human scalp hair and three different types of water samples: groundwater, stream water and tap water. The data presented in the article are raw isotope data of water and hair samples in tabulated manner and interpolated isoscapes generated using those data. Further information related to the datasets and discussion about them can be found in the related research article entitled "Spatial variations in oxygen and hydrogen isotopes in waters and human hair across South Korea" [1].

20.
Sci Total Environ ; 726: 138365, 2020 Jul 15.
Article in English | MEDLINE | ID: mdl-32320869

ABSTRACT

The spatial distribution of isotopic signatures in the form of isoscape is a valuable tool to map their spatial heterogeneity in various environmental settings. However, only limited information about δ18O and δ2H in water across South Korea is available and to our knowledge no study so far has tried to examine the isotopic heterogeneity of tap water and human scalp hair in South Korea. Here, we present the first national scale analyses of stream water, groundwater, tap water, and human scalp hair isoscapes for South Korea. Stream water, groundwater, tap water, and human scalp hair samples were collected from across South Korea. These samples were analyzed for δ18O and δ2H, and the isotopic data were then used to generate interpolated δ18O and δ2H isoscapes for South Korea. The results of linear regression analyses showed strong and significant relationships between δ18Ohair and δ18Owater (R2 = 0.83, P < 0.002) and between δ2Hhair and δ2Hwater (R2 = 0.74, P < 0.006), primarily reflecting a close co-relationship between water and hair. The slopes of linear regressions for δ18O (Δδ18Ohair/Δδ18Owater) and δ2H (Δδ2Hhair/Δδ2Hwater) suggested that approximately 27% of hydrogen and 36% of oxygen in hair keratin were derived from the local drinking water. Interpolated δ18O and δ2H isotope maps of stream water, groundwater, and tap water samples collected from across South Korea showed similar spatial patterns of isotope variability. These samples showed a clear latitudinal gradient with high isotopic values in the south which progressively decrease toward the north. The same trends were observed in hair isoscapes as well, and had gradients matching the isotopic pattern of water samples. The strong relationship between water and human hair, and the consistent spatial pattern between them suggest that hair isotope signatures in South Korea can be used in provenance- and forensic-related activities.


Subject(s)
Hydrogen/analysis , Oxygen , Hair/chemistry , Humans , Isotopes , Oxygen Isotopes/analysis , Republic of Korea
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