scholarly journals Potential neuroprotective strategies against tauopathy

2012 ◽  
Vol 40 (4) ◽  
pp. 656-660 ◽  
Author(s):  
Jeanna M. Wheeler ◽  
Chris R. Guthrie ◽  
Brian C. Kraemer
Keyword(s):  
Drug Target ◽  
Mammalian Cell Culture ◽  
Model Organisms ◽  
Tau Pathology ◽  
C Elegans ◽  
Neuroprotective Strategies ◽  
The Central Nervous System ◽  
Ad Alzheimer’S Disease ◽  
T Tau

Tauopathies are neurodegenerative diseases, including AD (Alzheimer's disease) and FTLD-T (tau-positive frontotemporal lobar degeneration), with shared pathology presenting as accumulation of detergent-insoluble hyperphosphorylated tau deposits in the central nervous system. The currently available treatments for AD address only some of the symptoms, and do not significantly alter the progression of the disease, namely the development of protein aggregates and loss of functional neurons. The development of effective treatments for various tauopathies will require the identification of common mechanisms of tau neurotoxicity, and pathways that can be modulated to protect against neurodegeneration. Model organisms, such as Caenorhabditis elegans, provide methods for identifying novel genes and pathways that are involved in tau pathology and may be exploited for treatment of various tauopathies. In the present paper, we summarize data regarding characterization of MSUT2 (mammalian suppressor of tau pathology 2), a protein identified in a C. elegans tauopathy model and subsequently shown to modify tau toxicity in mammalian cell culture via the effects on autophagy pathways. MSUT2 represents a potential drug target for prevention of tau-related neurodegeneration.

The glycomes of Caenorhabditis elegans and other model organisms

2002 ◽  
Vol 69 ◽  
pp. 117-134 ◽  
Author(s):  
Stuart M. Haslam ◽  
David Gems ◽  
Howard R. Morris ◽  
Anne Dell
Keyword(s):  
Caenorhabditis Elegans ◽  
Current Knowledge ◽  
Structural Data ◽  
Model Organisms ◽  
Entire Genome ◽  
C Elegans ◽  
The Face ◽  
Area Of Concern ◽  
Nematode Worm

There is no doubt that the immense amount of information that is being generated by the initial sequencing and secondary interrogation of various genomes will change the face of glycobiological research. However, a major area of concern is that detailed structural knowledge of the ultimate products of genes that are identified as being involved in glycoconjugate biosynthesis is still limited. This is illustrated clearly by the nematode worm Caenorhabditis elegans, which was the first multicellular organism to have its entire genome sequenced. To date, only limited structural data on the glycosylated molecules of this organism have been reported. Our laboratory is addressing this problem by performing detailed MS structural characterization of the N-linked glycans of C. elegans; high-mannose structures dominate, with only minor amounts of complex-type structures. Novel, highly fucosylated truncated structures are also present which are difucosylated on the proximal N-acetylglucosamine of the chitobiose core as well as containing unusual Fucα1–2Gal1–2Man as peripheral structures. The implications of these results in terms of the identification of ligands for genomically predicted lectins and potential glycosyltransferases are discussed in this chapter. Current knowledge on the glycomes of other model organisms such as Dictyostelium discoideum, Saccharomyces cerevisiae and Drosophila melanogaster is also discussed briefly.

scholarly journals Isolation and characterization of extracellular vesicles from Caenorhabditis elegans for multi-omic analysis

2018 ◽  
Author(s):  
Joshua C. Russell ◽  
Gennifer E. Merrihew ◽  
Julia E. Robbins ◽  
Nadia Postupna ◽  
Tyek-Kyun Kim ◽  
...  
Keyword(s):  
Cell Culture ◽  
Caenorhabditis Elegans ◽  
Extracellular Vesicles ◽  
Mammalian Cell Culture ◽  
Model Systems ◽  
C Elegans ◽  
Isolation And Characterization ◽  
Transmission Electron ◽  
Invertebrate Model

AbstractCells from bacteria to human release vesicles into their extracellular environment. These extracellular vesicles (EVs) contain multiple classesof molecules, including nucleic acids, proteins, and lipids. The isolation and analysis of EV cargos from mammalian cell culture and liquid biopsysamples has become a powerful approach for uncovering the messages that are packaged into these organelles. However, this approach has not been tenable in invertebrate model systems due to lack of sufficient amounts of pure EVs. Here we report a robust and reproducible procedure to isolateEVs from Caenorhabditis elegans with yields similar to those obtained from human cell culture. Through nanoparticle tracking, transmission electron microscopy, flow cytometry, mass spectrometry, RNAseq, and immunoaffinity analysis we provide the first ever detailed characterization of C. elegans EV composition and demonstrate that C. elegans EVs share fundamentally similar properties with their mammalian counterparts. These include vesicle size, enrichment for lipid rafts, and similar types of RNA and protein cargos. This ability of isolate pure EVs on ascale amenable to multiple types of downstream analyses permits, multi-omics characterization of EV cargos in an invertebrate model system.

Neuropharmacological Characterization of Dioclea altissima Seed Lectin (DAL) in Mice: Evidence of Anxiolytic-like Effect Mediated by Serotonergic, GABAergic Receptors and NO Pathway

2020 ◽  
Vol 26 (31) ◽  
pp. 3895-3904
Author(s):  
João R.C. Araújo ◽  
Adriana R. Campos ◽  
Marina de Barros M.V. Damasceno ◽  
Sacha A.A.R. Santos ◽  
Maria K.A. Ferreira ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Elevated Plus Maze ◽  
Biological Activities ◽  
Plant Lectins ◽  
Plus Maze ◽  
Marble Burying ◽  
Gabaergic Receptors ◽  
The Central Nervous System ◽  
Hole Board

Background: Plant lectins have shown promising biological activities in the central nervous system (CNS). Objective: This study evaluated the effect of DAL, a lectin isolated from the seeds of the Dioclea altissima species, having binding affinity to D-glucose or D-mannose residues, on mice behavior. Methods: Mice (n=6/group) were treated (i.p.) with DAL (0.25, 0.5 or 1 mg/kg) or vehicle and subjected to several tests (open field/OFT, marble-burying/MBT, hole-board/HBT, elevated plus maze/PMT, tail suspension/ TST, forced swimming/FST or rotarod/RRT). Pizotifen, cyproheptadine, flumazenil, L-NAME, 7-NI, Larginine or yohimbine were administered 15 min before DAL (0.5 mg/kg) and the animals were evaluated on PMT. It was also verified whether the DAL effect depended on its structural integrity and ability to interact with carbohydrates. Results: The results showed there were no neurobehavioral changes in the mice at the RRT, FST and locomotion in the OFT. DAL (0.25, 0.5 or 1 mg/kg) increased the behavior of grooming and rearing in the OFT, head dips in the HBT, pedalling in the TST and decreased the number of marbles hidden in the MBT. In the PMT, DAL (0.25, 0.5 and 1 mg/kg) and Diazepam increased the frequency of entries in the open arms and the time of permanence in the open arms without affecting the locomotor activity. The effect of DAL was dependent on carbohydrate interaction and protein structure integrity and it prevented by pizotifen, cyproheptadine, flumazenil, L-NAME and 7-NI, but not by L-arginine or yohimbine. Conclusion: DAL was found to have an anxiolytic-like effect mediated by the 5-HT and GABAergic receptors and NO pathway.

Neurochemistry of L-Glutamate Transport in the CNS: A Review of Thirty Years of Progress

2001 ◽  
Vol 66 (9) ◽  
pp. 1315-1340 ◽  
Author(s):  
Vladimir J. Balcar ◽  
Akiko Takamoto ◽  
Yukio Yoneda
Keyword(s):  
Molecular Biology ◽  
Glutamate Transport ◽  
Mammalian Brain ◽  
Activity Data ◽  
System A ◽  
Recent Developments ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Disease Analysis

The review highlights the landmark studies leading from the discovery and initial characterization of the Na+-dependent "high affinity" uptake in the mammalian brain to the cloning of individual transporters and the subsequent expansion of the field into the realm of molecular biology. When the data and hypotheses from 1970's are confronted with the recent developments in the field, we can conclude that the suggestions made nearly thirty years ago were essentially correct: the uptake, mediated by an active transport into neurons and glial cells, serves to control the extracellular concentrations of L-glutamate and prevents the neurotoxicity. The modern techniques of molecular biology may have provided additional data on the nature and location of the transporters but the classical neurochemical approach, using structural analogues of glutamate designed as specific inhibitors or substrates for glutamate transport, has been crucial for the investigations of particular roles that glutamate transport might play in health and disease. Analysis of recent structure/activity data presented in this review has yielded a novel insight into the pharmacological characteristics of L-glutamate transport, suggesting existence of additional heterogeneity in the system, beyond that so far discovered by molecular genetics. More compounds that specifically interact with individual glutamate transporters are urgently needed for more detailed investigations of neurochemical characteristics of glutamatergic transport and its integration into the glutamatergic synapses in the central nervous system. A review with 162 references.

scholarly journals Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽  
2003 ◽  
Vol 163 (2) ◽  
pp. 571-580 ◽  
Author(s):  
William B Raich ◽  
Celine Moorman ◽  
Clay O Lacefield ◽  
Jonah Lehrer ◽  
Dusan Bartsch ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Caenorhabditis Elegans ◽  
Trisomy 21 ◽  
Gene Dosage ◽  
Inducible Promoters ◽  
C Elegans ◽  
Dual Specificity ◽  
Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

scholarly journals Functional Characterization of the Adenylyl Cyclase Genesgs-1by Analysis of a Mutational Spectrum inCaenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Celine Moorman ◽  
Ronald H A Plasterk
Keyword(s):  
Life Span ◽  
Adenylyl Cyclase ◽  
Neuronal Degeneration ◽  
Functional Characterization ◽  
Adenylyl Cyclases ◽  
Loss Of Function ◽  
C Elegans ◽  
Larval Stages ◽  
Pharyngeal Pumping

AbstractThe sgs-1 (suppressor of activated Gαs) gene encodes one of the four adenylyl cyclases in the nematode C. elegans and is most similar to mammalian adenylyl cyclase type IX. We isolated a complete loss-of-function mutation in sgs-1 and found it to result in animals with retarded development that arrest in variable larval stages. sgs-1 mutant animals exhibit lethargic movement and pharyngeal pumping and (while not reaching adulthood) have a mean life span that is >50% extended compared to wild type. An extensive set of reduction-of-function mutations in sgs-1 was isolated in a screen for suppressors of a neuronal degeneration phenotype induced by the expression of a constitutively active version of the heterotrimeric Gαs subunit of C. elegans. Although most of these mutations change conserved residues within the catalytic domains of sgs-1, mutations in the less-conserved transmembrane domains are also found. The sgs-1 reduction-of-function mutants are viable and have reduced locomotion rates, but do not show defects in pharyngeal pumping or life span.

scholarly journals Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 980
Author(s):  
Ka-Young Kim ◽  
Ki-Young Shin ◽  
Keun-A. Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Web Of Science ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Blood Biomarkers ◽  
Cell Lineages ◽  
The Central Nervous System ◽  
New Biomarkers ◽  
T Tau

Alzheimer’s disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595–2.474), total-tau (SMD = 1.224, 95% CI: 0.534–1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795–4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.

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