108 results on '"Plaas, M."'
Search Results
2. Depression-associated Negr1 gene-deficiency induces alterations in the monoaminergic neurotransmission enhancing time-dependent sensitization to amphetamine in mice
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Kaare, M., Jayaram, M., Jagomäe, T., Singh, K., Kilk, K., Leevik, M., Varul, J., Leidmaa, E., Visnapuu, T., Nõmm, H., Rähn, K., Plaas, M., Lilleväli, K., Schäfer, M.K.E., Philips, M.A., and Vasar, E.
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- 2022
- Full Text
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3. Theme 06 - Tissue Biomarkers.
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Bobeva, Y., Castro-Gomez, S., Kittipeerapat, N., Heneka, M., Weydt, P., Gaur, N., Wang, M., Steinbach, R., Riemenschneider, H., Edbauer, D., Plaas, M., Witte, O., Brill, M., Großkreutz, J., Monteiro Lopes, D., A. Conceição, V., Lopes, C. S., Gromicho, M., Santos, N. C., and . Carvalho, F. A
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AMYOTROPHIC lateral sclerosis ,BIOMARKERS ,HIGH density lipoproteins - Abstract
Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis. Title is CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis. Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: a more than 20-year follow-up of the Swedish AMORIS cohort. [Extracted from the article]
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- 2022
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4. LIMBIC SYSTEM ASSOCIATED MEMBRANE PROTEIN (LSAMP) AND WOLFRAMIN (WFS1) AS THE POTENTIAL TARGETS FOR INFLUENCING EMOTIONAL DISORDERS: I12
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Vasar, E., Visnapuu, T., Luuk, H., Terasmaa, A., Raud, S., Innos, J., Plaas, M., Philips, M.-A., and Kõks, S.
- Published
- 2011
5. Lack of functional wolframin causes drop in plasmalemmal sodium-calcium exchanger type 1 expression at early stage in rat model of Wolfram syndrome
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Kurekova, S., primary, Plaas, M., additional, and Cagalinec, M., additional
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- 2020
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6. The Sino-Nasal Outcome Test-22: translation and validation in an Estonian population
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Plaas, M., primary and Kasenomm, P., additional
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- 2019
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7. microRNA-146a is linked to the production of IgE in mice but not in atopic dermatitis patients
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Carreras-Badosa, G., Runnel, T., Plaas, M., Kärner, J., Rückert, B., Lättekivi, F., Kõks, S., Cezmi, A.A., Kingo, K., Rebane, A., Carreras-Badosa, G., Runnel, T., Plaas, M., Kärner, J., Rückert, B., Lättekivi, F., Kõks, S., Cezmi, A.A., Kingo, K., and Rebane, A.
- Abstract
Background: Atopic dermatitis (AD) is a chronic and complex inflammatory skin disease. At least two AD subtypes have been described: allergic (characterized by Type‐2‐cell‐mediated immunity and increased immunoglobulin E [IgE]) and non‐allergic (characterized by both Type‐2‐cell and Type‐1/17‐cell‐mediated immunity and normal IgE levels). MicroRNA (miR) are small non‐coding RNA molecules involved in genetic regulation. MiR‐146a negatively regulates inflammatory responses during chronic skin inflammation, however, its role in the modulation of immune responses in AD is uncovered. As recently miR‐146a was shown to promote IgE class switch in B cells in mice, we aimed to test whether there is association between miR‐ 146a and increased IgE levels in AD. Method: Serum samples from miR‐146a−/− and wild‐type C57BL/ 6J mice with MC903‐induced AD‐like inflammation were analysed (N = 8 mice/group) for IgE and cytokine levels. Additionally, 32 serum samples from AD patients were also analysed. Subjects were split into allergic (N = 22) and non‐allergic (N = 10) according to IgE threshold of 150 IU/mL. MiR‐146a relative expression was quantified by real‐time PCR, IgE and human IL‐12p40 by ELISA and mouse cytokines by Bioplex. Results: MiR‐146a−/− mice showed decreased IgE and increased IL‐ 12p40 serum levels (P < 0.001), while there were no changes in other detected cytokines. Human miR‐146a expression was not significantly different between allergic and non‐allergic subgroups divided based on serum IgE level. However, we observed a negative correlation of serum miR‐146a and IgE levels (P < 0.05) in allergic AD patients. In the allergic subgroup, miR‐146a expression remained independently negatively associated with IgE (β = −0.488, P < 0.05) after adjusting for confounding variables as gender. Conclusion: Low IgE and high IL‐12p40 serum levels in miR‐ 146a−/− mice indicate that miR‐146a is needed for the production of IgE and associated with the regulation of Type‐1/17‐cell‐me
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- 2018
8. P467Deletion of Wolframin1 results in remodelling of plasma membrane and mitochondrial cristae in cardiac myocytes
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Notovova, M, primary, Gogichaishvili, N, additional, Barok, D, additional, Plaas, M, additional, Zahradnik, I, additional, and Cagalinec, M, additional
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- 2018
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9. Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats
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Sutt, S., Raud, S., Abramov, U., Innos, J., Luuk, H., Plaas, M., Koks, S., Zilmer, K., Mahlapuu, R., Zilmer, M., and Vasar, E.
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Anxiety -- Psychological aspects ,Corticosterone -- Psychological aspects ,Gene expression -- Analysis ,Oxidative stress -- Physiological aspects ,Pharmaceuticals and cosmetics industries ,Psychology and mental health - Published
- 2010
10. Kloonembrüote ja in vitro viljastatud embrüote RNA sünteesi erinevused
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Lilleoja, R., Reimann, E., Nõmm, M., Plaas, M., Ivask, M., Pärn, P., Häling, A., Jaakma, Ü., Kõks, S., Lilleoja, R., Reimann, E., Nõmm, M., Plaas, M., Ivask, M., Pärn, P., Häling, A., Jaakma, Ü., and Kõks, S.
- Abstract
Tuuma siirdamise teel kloonimise efektiivsus on väga madal, sageli on elussündide osakaal alla 1%(Watanabe, 2013). Embrüonaalses arengus on väga oluline etapp doonorraku tuuma ümberprogrammeerimine, mis ei pruugi kloonimise puhul toimuda täies ulatuses. Puuduliku ümberprogrammeerimise tulemusena peetub kloonembrüote kasv erinevates arenguetappides ning lõpeb sageli loote surmaga (Chitwood jt, 2013; Graf jt, 2014). Suurem osa probleemidest avaldub varastes arenguetappides. Kuid ka hilisemas arengus võib avalduda kõrvalekaldeid normaalsest arengust–sageli esineb kloontiinuste puhul platsentoomide suurenemist ja nende arvu vähenemist, suurenenud läbimõõduga nabanööri ja ka vasikad ise on keskmisest suuremad. Sellist nähtust nimetatakse suure järglase sündroomiks (Chitwood jt, 2013; Graf jt, 2014).
- Published
- 2016
11. 49 Effects of culture conditions and gene transfection on the development of bovine somatic cell nuclear transfer embryos
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Pärn, P., Plaas, M., Nõmm, M., Jaakma, Ü., Kõks, S., Pärn, P., Plaas, M., Nõmm, M., Jaakma, Ü., and Kõks, S.
- Abstract
Somatic cell nucleus transfer (SCNT) and in vitro culture of reconstructed embryos are the pivotal steps for successful cloning and generation of transgenic cattle. The aim of the study was to determine the influence of different cell fusion parameters, maturation, and culture conditions and the type of a cell line (bovine fetal fibroblast cell lines with or without gene transfection) on SCNT blastocyst development. Slaughterhouse-derived oocytes were matured for 17 h in TCM-199 (Sigma, St. Louis, MO, USA) supplemented with 0.05 µg mL–1 of epidermal growth factor (EGF) and 15 IU mL–1 of hCG/eCG (Intervet, PG600) or 10 µg mL–1 of FSH and 12.5 mU mL–1 of LH (Sioux Biochemical Inc., Sioux Center, IA, USA). Four fetal fibroblast cell lines (4 to 5 passages) and identical cell lines transfected with plasmid containing either human erythropoietin, FSH, growth hormone, or insulin-coding cDNA under β-casein promoter (7 to 9 passages) were used for SCNT. Cell fusion was induced by 2 direct-current pulses in 0.5 or 0.2 micro fusion chambers (Eppendorf Multiporator) using one of the following treatments: 100V for 15 µs (F1), 65V for 25 µs (F2), 65V for 20 µs (F3; all in a 0.5-mm chamber), or 36V for 25 µs (F4; 0.2-mm chamber). Fused complexes were activated with 4 µg mL–1 of Ca-ionophore for 4 min and then incubated for 5 h in 2 mM DMAP. The embryos were cultured in SOFaaci medium (Holm et al. 1999) or in commercial SOF medium (Minitüb GmbH, Tiefenbach, Germany) for 7 days. Data were analysed by ANOVA and the chi-square test. The results of the study showed that the cleavage rate of the reconstructed embryos was influenced by the fusion regimen (P < 0.05) but not by the donor cell type (P < 0.05). Treatments F2 and F3 resulted in cleavage rates higher (P < 0.05) than F1 and F4 (77.2, 82.0, 62.8, and 63.1%, respectively). Blastocyst yield was not significantly influenced by the different in vitro maturation (IVM) media – altogether, addition of FSH/LH resulted in 14.6% (158/107
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- 2013
12. Valproic acid does not affect decreased insulin secretion in WFS1-deficient pancreatic islets
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Kõks, S., Ivask, M., Hugill, A., Terasmaa, A., Plaas, M., Vasar, E., Kõks, S., Ivask, M., Hugill, A., Terasmaa, A., Plaas, M., and Vasar, E.
- Abstract
Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the wolframin (WFS1) gene. WFS1 negatively regulates endoplasmic reticulum (ER) stress signalling and therefore have a role in the pathogenesis of diabetes. Valproic acid (VPA), a widely used anticonvulsant and mood-stabilizing drug, normalized the glucose intolerance in Wfs1 mutant mice, but had no effect on the course of glucose tolerance in wild-type (WT) mice. The aim of this study was to investigate insulin secretion in isolated pancreatic islets of WFS1-deficient (Wfs1KO) mice and also evaluate insulin secretion in the presence of VPA. In addition, the content of proinsulin in the isolated islets was measured. In general Wfs1KO pancreatic islets secreted less insulin compared to WT and Wfs1HZ islets. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. We found significantly reduced insulin secretion in Wfs1 mutants and no effect of VPA treatment. This study was supported by the Frontiers of Functional Genomics and by The European Regional Development Fund.
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- 2013
13. Wfs1-deficient mice display altered function of serotonergic system and increased behavioral response to antidepressants
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Visnapuu, T., Raud, S., Loomets, M., Reimets, R., Sütt, S., Luuk, H., Plaas, M., Kõks, S., Volke, V., Alttoa, A., Harro, J., Vasar, E., Visnapuu, T., Raud, S., Loomets, M., Reimets, R., Sütt, S., Luuk, H., Plaas, M., Kõks, S., Volke, V., Alttoa, A., Harro, J., and Vasar, E.
- Abstract
It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.
- Published
- 2013
14. Evidence for impaired function of dopaminergic system in Wfs1-deficient mice
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Visnapuu, T., Plaas, M., Reimets, R., Raud, S., Terasmaa, A., Kõks, S., Sütt, S., Luuk, H., Hundahl, C.A., Eskla, K-L, Altpere, A., Alttoa, A., Harro, J., Vasar, E., Visnapuu, T., Plaas, M., Reimets, R., Raud, S., Terasmaa, A., Kõks, S., Sütt, S., Luuk, H., Hundahl, C.A., Eskla, K-L, Altpere, A., Alttoa, A., Harro, J., and Vasar, E.
- Abstract
Immunohistological studies suggest abundant expression of Wfs1 protein in neurons and nerve fibers that lie in the vicinity of dopaminergic (DA-ergic) fibers and neurons. Therefore, we sought to characterize the function of DA-ergic system in Wfs1-deficient mice. In wild-type mice, amphetamine, an indirect agonist of DA, caused significant hyperlocomotion and increase in tissue DA levels in the dorsal and ventral striatum. Both effects of amphetamine were significantly blunted in homozygous Wfs1-deficient mice. Motor stimulation caused by apomorphine, a direct DA receptor agonist, was somewhat stronger in Wfs1-deficient mice compared to their wild-type littermates. However, apomorphine caused a similar reduction in levels of DA metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) in the dorsal and ventral striatum in all genotypes. Behavioral sensitization to repeated treatment with amphetamine (2.5 mg/kg) was observed in wild-type, but not in Wfs1-deficient mice. The expression of DA transporter gene (Dat) mRNA was significantly lower in the midbrain of male and female homozygous mice compared to wild-type littermates. Altogether, the blunted effects of amphetamine and the reduced gene expression of DA transporter are probably indicative of an impaired functioning of the DA-ergic system in Wfs1-deficient mice.
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- 2013
15. S.2.05 Wolframin (WFS1) deficient mice display increased anxiety and reduced adaptation in a novel environment
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Vasar, E., Kõks, S., Luuk, H., Plaas, M., Sütt, S., Raud, S., Kurrikoff, K., Abramov, U., and Innos, J.
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- 2009
- Full Text
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16. Lower anxiety and a decrease in agonistic behaviour in Lsamp-deficient mice
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Innos, J., Philips, M-A, Leidmaa, E., Heinla, I., Raud, S., Reemann, P., Plaas, M., Nurk, K., Kurrikoff, K., Matto, V., Visnapuu, T., Mardi, P., Kõks, S., Vasar, E., Innos, J., Philips, M-A, Leidmaa, E., Heinla, I., Raud, S., Reemann, P., Plaas, M., Nurk, K., Kurrikoff, K., Matto, V., Visnapuu, T., Mardi, P., Kõks, S., and Vasar, E.
- Abstract
In rodents, the Lsamp gene has been implicated in trait anxiety, fear reaction and fear conditioning. Human data link the LSAMP gene to several psychiatric disorders. In this study, we presented a general phenotypic characterization of Lsamp gene-deficient mouse line, created by deleting exon 1b. These mice displayed no gross sensory-motor deficiencies, no overt abnormalities and performed normally in memory and learning tests. However, they responded with increased activity to new environments. Moreover, they displayed reduced anxiety and notable deviations in social behaviour, such as lack of whisker trimming, reduced aggressiveness and reduced dominance. One possible explanation for the anxiolytic-like effect of the deletion of the Lsamp gene is a shift in balance in the Gabra1 and Gabra2 genes in the temporal lobe in favor of the Gabra2 transcript, encoding α2 subunit of GABAA receptors that mediate the stimulating effect of GABA agonists. The overall phenotype of Lsamp-deficient mice, characterized by decreased anxiety and several alterations in social behaviour, makes them a good model for studying the molecular mechanisms behind inadequate social behaviours observed in several psychiatric disorders.
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- 2011
17. Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice
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Kõks, S., Soomets, U., Plaas, M., Terasmaa, A., Noormets, K., Tillmann, V., Vasar, E., Fernandes, C., Schalkwyk, L.C., Kõks, S., Soomets, U., Plaas, M., Terasmaa, A., Noormets, K., Tillmann, V., Vasar, E., Fernandes, C., and Schalkwyk, L.C.
- Abstract
The Wfs1 gene codes for a protein with unknown function, but deficiency in this protein results in a range of neuropsychiatric and neuroendocrine syndromes. In the present study we aimed to find the functional networks influenced by Wfs1 in the hypothalamus. We performed gene expression profiling (Mouse Gene 1.0 ST Arrays) in Wfs1-deficient mice; 305 genes were differentially expressed with nominal P value < 0.01. FDR (false discovery rate)-adjusted P values were significant (0.007) only for two genes: C4b (t=9.66) and Wfs1 (t = −9.03). However, several genes related to G protein signaling were very close to the FDR-adjusted significance level, such as Rgs4 (regulator of G protein signaling 4) that was downregulated (−0.34, t = −5.4) in Wfs1-deficient mice. Changes in Rgs4 and C4b expression were confirmed by QRT-PCR. In humans, Rgs4 is in the locus for bipolar disease (BPD), and its expression is downregulated in BPD. C4b is a gene related to the neurodegenerative diseases. Functional analysis including the entire data set revealed significant alterations in the canonical pathway “G protein-coupled receptor signaling.” The gene expression profile in the hypothalami of the Wfs1 mutant mice was significantly similar to the profiles of following biological functions: psychological disorders, bipolar disorder, mood disorder. In conclusion, hypothalamic gene expression profile resembles with some molecular pathways functionally related to the clinical syndromes in the Wolfram syndrome patients.
- Published
- 2011
18. Limbic system associated membrane protein (LSAMP) and wolframin (WFS1) as the potential targets for influencing emotional disorders
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Vasar, E., Visnapuu, T., Luuk, H., Terasmaa, A., Raud, S., Innos, J., Plaas, M., Philips, M-A, Kõks, S., Vasar, E., Visnapuu, T., Luuk, H., Terasmaa, A., Raud, S., Innos, J., Plaas, M., Philips, M-A, and Kõks, S.
- Abstract
Invited Lecture
- Published
- 2011
19. Myg1-deficient mice display alterations in stress-induced responses and reduction of sex-dependent behavioural differences
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Philips, M-A, Abramov, U., Lilleväli, K., Luuk, H., Kurrikoff, K., Raud, S., Plaas, M., Innos, J., Puussaar, T., Kõks, S., Philips, M-A, Abramov, U., Lilleväli, K., Luuk, H., Kurrikoff, K., Raud, S., Plaas, M., Innos, J., Puussaar, T., and Kõks, S.
- Abstract
Myg1 (Melanocyte proliferating gene 1) is a highly conserved and ubiquitously expressed gene, which encodes a protein with mitochondrial and nuclear localization. In the current study we demonstrate a gradual decline of Myg1 expression during the postnatal development of the mouse brain that suggests relevance for Myg1 in developmental processes. To study the effects of Myg1 loss-of-function, we created Myg1-deficient (−/−) mice by displacing the entire coding sequence of the gene. Initial phenotyping, covering a multitude of behavioural, cognitive, neurological, physiological and stress-related responses, revealed that homozygous Myg1 (−/−) mice are vital, fertile and display no gross abnormalities. Myg1 (−/−) mice showed an inconsistent pattern of altered anxiety-like behaviour in different tests. The plus-maze and social interaction tests revealed that male Myg1 (−/−) mice were significantly less anxious than their wild-type littermates; female (−/−) mice showed increased anxiety in the locomotor activity arena. Restraint-stress significantly reduced the expression of the Myg1 gene in the prefrontal cortex of female wild-type mice and restrained female (−/−) mice showed a blunted corticosterone response, suggesting involvement of Myg1 in stress-induced responses. The main finding of the present study was that Myg1 invalidation decreases several behavioural differences between male and female animals that were obvious in wild-type mice, indicating that Myg1 contributes to the expression of sex-dependent behavioural differences in mice. Taken together, we provide evidence for the involvement of Myg1 in anxiety- and stress-related responses and suggest that Myg1 contributes to the expression of sex-dependent behavioural differences.
- Published
- 2010
20. Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABAA receptors in Wfs1-deficient mice
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Raud, S., Sütt, S., Luuk, H., Plaas, M., Innos, J., Kõks, S., Vasar, E., Raud, S., Sütt, S., Luuk, H., Plaas, M., Innos, J., Kõks, S., and Vasar, E.
- Abstract
Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. In clinical studies a relation between mutations in the Wfs1 gene and increased susceptibility for mood disorders has been established. According to our previous studies, mice lacking Wfs1 gene displayed increased anxiety in stressful environment. As the GABA-ergic system plays a significant role in the regulation of anxiety, we analyzed the expression of GABA-related genes in the forebrain structures of wild-type and Wfs1-deficient mice. Experimentally naïve Wfs1-deficient animals displayed a significant down-regulation of α1 (Gabra1) and α2 (Gabra2) subunits of GABAA receptors in the temporal lobe and frontal cortex. Exposure of wild-type mice to the elevated plus-maze decreased levels of Gabra1 and Gabra2 genes in the temporal lobe. A similar tendency was also established in the frontal cortex of wild-type animals exposed to behavioral test. In Wfs1-deficient mice the elevated plus-maze exposure did not induce further changes in the expression of Gabra1 and Gabra2 genes. By contrast, the expression of Gad1 and Gad2 genes, enzymes responsible for the synthesis of GABA, was not significantly affected by the exposure of mice to the elevated plus-maze or by the invalidation of Wfs1 gene. Altogether, the present study demonstrates that increased anxiety of Wfs1-deficient mice is probably linked to reduced expression of Gabra1 and Gabra2 genes in the frontal cortex and temporal lobe.
- Published
- 2009
21. The effects of chronic administration of ephedrone (methcathinone) and manganese in mice
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Asser, A., Kõks, S., Haaparanta-Solin, M., Grönroos, T., Pakkanen, A., Nairismägi, J., Plaas, M., Soomets, U., Sauk, M., Piip, P., Eltermaa, M., Lindmäe, H., Taba, P., Asser, A., Kõks, S., Haaparanta-Solin, M., Grönroos, T., Pakkanen, A., Nairismägi, J., Plaas, M., Soomets, U., Sauk, M., Piip, P., Eltermaa, M., Lindmäe, H., and Taba, P.
- Abstract
No abstract available
- Published
- 2009
22. Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway
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Kõks, S., Soomets, U., Paya-Cano, J.L., Fernandes, C., Luuk, H., Plaas, M., Terasmaa, A., Tillmann, V., Noormets, K., Vasar, E., Schalkwyk, L.C., Kõks, S., Soomets, U., Paya-Cano, J.L., Fernandes, C., Luuk, H., Plaas, M., Terasmaa, A., Tillmann, V., Noormets, K., Vasar, E., and Schalkwyk, L.C.
- Abstract
The aim of present study was to describe changes in gene expression in the temporal lobe of mice induced by deletion of the Wfs1 gene. Temporal lobes samples were analyzed using Affymetrix Mouse Genome 420 2 GeneChips and expression profiles were functionally annotated with GSEA and Ingenuity Pathway Analysis. We found that Wfs1 mutant mice are significantly smaller (20.9 ± 1.6 g) than their wild-type counterparts (31.0 ± 0.6 g, P < 0.0001). This difference existed in 129S6 and C57B6 backgrounds. Interestingly, microarray analysis identified upregulation of growth hormone (GH) transcripts and functional analysis revealed activation of GH pathways. In line with microarray data, the level of IGF-1 in the plasma of Wfs1 mutant mice was significantly increased (P < 0.05). Thus, Wfs1 deletion induces growth retardation, whereas the GH pathway is activated. To test the interaction between the Wfs1 deletion and genomic background, mutant mice were backcrossed to two different genetic backgrounds. In line with previous studies, an interaction between a gene knockout and genetic background was found in gene expression profiles in the congenic region. However, genetic background did not alter the effect of the Wfs1 mutation on either body weight or GH pathway activation. Further studies are needed to describe biochemical and molecular changes of the growth hormone axis as well as in other hormones to clarify their role in growth retardation in the Wfs1 mutant mice.
- Published
- 2009
23. Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome
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Luuk, H., Kõks, S., Plaas, M., Hannibal, J., Rehfeld, J.F., Vasar, E., Luuk, H., Kõks, S., Plaas, M., Hannibal, J., Rehfeld, J.F., and Vasar, E.
- Abstract
Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. Patients with Wolfram syndrome display considerable clinical pleiomorphism, and symptoms such as neurological complications and psychiatric disorders are common. In the present study we have characterized Wfs1 expression pattern in the mouse central nervous system by using a combination of immunohistochemistry on wild‐type mice and X‐Gal staining of Wfs1 knockout mice with targeted insertion of the lacZ reporter. We identified a robust enrichment of Wfs1 protein in the central extended amygdala and ventral striatum. Prominent Wfs1 expression was seen in the hippocampal CA1 region, parasubiculum, superficial part of the second and third layers of the prefrontal cortex and proisocortical areas, hypothalamic magnocellular neurosecretory system, and central auditory pathway. Wfs1 expression was also detected in numerous brainstem nuclei and in laminae VIII and IX of the spinal cord. Wfs1‐positive nerve fibers were found in the medial forebrain bundle, reticular part of the substantia nigra, globus pallidus, posterior caudate putamen, lateral lemniscus, alveus, fimbria, dorsal hippocampal commissure, subiculum, and to a lesser extent in the central sublenticular extended amygdala, compact part of substantia nigra, and ventral tegmental area. The neuroanatomical findings suggest that the lack of Wfs1 protein function can be related to several neurological and psychiatric symptoms found in Wolfram syndrome. Enrichment of Wfs1 protein in the central extended amygdala suggests a role in the modulation of anxiety and fear.
- Published
- 2008
24. Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice
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Plaas, M., Karis, A., Innos, J., Rebane, E., Baekelandt, V., Vaarmann, A., Luuk, H., Vasar, E., Kõks, S., Plaas, M., Karis, A., Innos, J., Rebane, E., Baekelandt, V., Vaarmann, A., Luuk, H., Vasar, E., and Kõks, S.
- Abstract
Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum, and reduced levels of dopamine in the mesolimbic system. The present study confirms that SNCA plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age-related decline in specific motor performance. The generated mouse line has a potential to become a model for PD with comparable time course and phenotype.
- Published
- 2008
25. 49 EFFECTS OF CULTURE CONDITIONS AND GENE TRANSFECTION ON THE DEVELOPMENT OF BOVINE SOMATIC CELL NUCLEAR TRANSFER EMBRYOS
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Pärn, P., primary, Plaas, M., additional, Nõmm, M., additional, Jaakma, Ü., additional, and Kõks, S., additional
- Published
- 2013
- Full Text
- View/download PDF
26. Cat odor exposure induces distinct changes in the exploratory behavior and Wfs1 gene expression in C57Bl/6 and 129Sv mice
- Author
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Raud, S., Sütt, S., Plaas, M., Luuk, H., Innos, J., Philips, M-A, Kõks, S., Vasar, E., Raud, S., Sütt, S., Plaas, M., Luuk, H., Innos, J., Philips, M-A, Kõks, S., and Vasar, E.
- Abstract
129Sv and C57Bl/6 (Bl6) strains are two most widely used inbred mice strains for generation of transgenic animals. The present study confirms the existence of substantial differences in the behavior of these two mice strains. The exploratory behavior of Bl6 mice in a novel environment was significantly higher compared to 129Sv mice. The exposure of mice to cat odor-induced an anxiety-like state in Bl6, but not in 129Sv mice. The levels of Wfs1 gene expression did not differ in the prefrontal cortex, mesolimbic area and temporal lobe of experimentally naive Bl6 and 129Sv mice. However, after cat odor exposure the expression of Wfs1 gene was significantly lower in the mesolimbic area and temporal lobe of Bl6 mice compared to 129Sv strain. Dynamics of Wfs1 gene expression and exploratory behavior suggest that the down-regulation of Wfs1 gene in Bl6 mice might be related to the increased anxiety. Further studies are needed to test the robustness and possible causal relationship of this finding.
- Published
- 2007
27. Heterozygous mice with Ric-8 mutation exhibit impaired spatial memory and decreased anxiety
- Author
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Tõnissoo, T., Kõks, S., Meier, R., Raud, S., Plaas, M., Vasar, E., Karis, A., Tõnissoo, T., Kõks, S., Meier, R., Raud, S., Plaas, M., Vasar, E., and Karis, A.
- Abstract
Ric-8 is a guanine nucleotide exchange factor for a subset of Gα proteins and it is required to maintain Gαq and the Gαs pathways in functional state. In adult mice Ric-8 is expressed in regions involved in the regulation of behavior (neocortex, cingulate cortex and hippocampus). As Ric-8 is shown to regulate neuronal transmitter release, the aim of present study was to perform behavioral analysis of ric-8 mutant. Homozygous (−/−) ric-8 mutant mice are not viable and die in early embryonic development, therefore for behavioral analysis heterozygous (+/−) ric-8 mutant mice were used. We found decreased anxiety of ric-8 heterozygous mice in light–dark compartment test where mutant mice significantly avoided the light compartment. In spatial learning paradigm (Morris water maze) the performance of ric-8 (+/−) mice was impaired. Namely, in the reversal test, ric-8 (+/−) mice exhibited significant delay to find the hidden platform compared to wild-type (wt) littermates. We did not find differences in the behavioral tests reflecting the motor abilities of mice (motor activity, rota-rod). Therefore, described alterations seem to be specific for anxiety and spatial learning. Based on these results we can conclude the importance of ric-8 in the regulation of memory and emotional behavior.
- Published
- 2006
28. Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway
- Author
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Kõks, S., primary, Soomets, U., additional, Paya-Cano, J. L., additional, Fernandes, C., additional, Luuk, H., additional, Plaas, M., additional, Terasmaa, A., additional, Tillmann, V., additional, Noormets, K., additional, Vasar, E., additional, and Schalkwyk, L. C., additional
- Published
- 2009
- Full Text
- View/download PDF
29. Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats
- Author
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Sütt, S., primary, Raud, S., additional, Abramov, U., additional, Innos, J., additional, Luuk, H., additional, Plaas, M., additional, Kõks, S., additional, Zilmer, K., additional, Mahlapuu, R., additional, Zilmer, M., additional, and Vasar, E., additional
- Published
- 2009
- Full Text
- View/download PDF
30. Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice
- Author
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Plaas, M., Karis, A., Innos, J., Rebane, E., Baekelandt, V., Vaarmann, A., Luuk, H., Eero Vasar, and Koks, S.
- Subjects
Mice, Inbred C57BL ,Motor Skills Disorders ,Substantia Nigra ,Aging ,Mice ,Dopamine ,Age Factors ,alpha-Synuclein ,Animals ,Point Mutation ,Mice, Transgenic ,Parkinson Disease ,Corpus Striatum - Abstract
Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum, and reduced levels of dopamine in the mesolimbic system. The present study confirms that SNCA plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age-related decline in specific motor performance. The generated mouse line has a potential to become a model for PD with comparable time course and phenotype.
31. RNA-sequencing of WFS1-deficient pancreatic islets shows downregulation of Trpm5.
- Author
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Ivask, M., Hugill, A., Plaas, M., Vasar, E., and Koks, S.
- Subjects
ISLANDS of Langerhans ,WOLFRAM syndrome - Abstract
An abstract of the article "RNA-sequencing of WFS1-deficient pancreatic islets shows downregulation of Trpm5" by M. Ivask, A. Hugill, M. Plaas, E. Vasar and S. Kõks is presented.
- Published
- 2014
32. 49 EFFECTS OF CULTURE CONDITIONS AND GENE TRANSFECTION ON THE DEVELOPMENT OF BOVINE SOMATIC CELL NUCLEAR TRANSFER EMBRYOS.
- Author
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Pärn, P., Plaas, M., Nõmm, M., Jaakma, Ü., and Kõks, S.
- Subjects
- *
GENE transfection , *SOMATIC cells - Abstract
An abstract of the study "Effects of Culture Conditions and Gene Transfection on the Development of Bovine Somatic Cell Nuclear Transfer Embryos," by M. Plaas et al, is presented.
- Published
- 2012
- Full Text
- View/download PDF
33. The IgLON family of cell adhesion molecules expressed in developing neural circuits ensure the proper functioning of the sensory system in mice.
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Singh K, Jayaram M, Hanumantharaju A, Tõnissoo T, Jagomäe T, Mikheim K, Muthuraman S, Gilbert SF, Plaas M, Schäfer MKE, Innos J, Lilleväli K, Philips MA, and Vasar E
- Subjects
- Animals, Mice, Female, Male, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cell Adhesion Molecules, Neuronal genetics, Cell Adhesion Molecules, Neuronal metabolism, Gene Expression Regulation, Developmental, Mice, Knockout
- Abstract
Deletions and malfunctions of the IgLON family of cell adhesion molecules are associated with anatomical, behavioral, and metabolic manifestations of neuropsychiatric disorders. We have previously shown that IgLON genes are expressed in sensory nuclei/pathways and that IgLON proteins modulate sensory processing. Here, we examined the expression of IgLON alternative promoter-specific isoforms during embryonic development and studied the sensory consequences of the anatomical changes when one of the IgLON genes, Negr1, is knocked out. At the embryonal age of E12.5 and E13.5, various IgLONs were distributed differentially and dynamically in the developing sensory areas within the central and peripheral nervous system, as well as in limbs and mammary glands. Sensory tests showed that Negr1 deficiency causes differences in vestibular function and temperature sensitivity in the knockout mice. Sex-specific differences were noted across olfaction, vestibular functioning, temperature regulation, and mechanical sensitivity. Our findings highlight the involvement of IgLON molecules during sensory circuit formation and suggest Negr1's critical role in somatosensory processing., (© 2024. The Author(s).)
- Published
- 2024
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34. ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
- Author
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Liiv M, Vaarmann A, Safiulina D, Choubey V, Gupta R, Kuum M, Janickova L, Hodurova Z, Cagalinec M, Zeb A, Hickey MA, Huang YL, Gogichaishvili N, Mandel M, Plaas M, Vasar E, Loncke J, Vervliet T, Tsai TF, Bultynck G, Veksler V, and Kaasik A
- Subjects
- Animals, Mice, Humans, Adenosine Triphosphate metabolism, Inositol 1,4,5-Trisphosphate Receptors metabolism, Inositol 1,4,5-Trisphosphate Receptors genetics, Mice, Knockout, NAD metabolism, Calcium Signaling, Wolfram Syndrome metabolism, Wolfram Syndrome genetics, Calcium metabolism, Mitochondria metabolism, Endoplasmic Reticulum metabolism, Neurons metabolism, Membrane Proteins metabolism, Membrane Proteins genetics
- Abstract
Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca
2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3 R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health., (© 2024. The Author(s).)- Published
- 2024
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35. A cost-effective and efficient ex vivo, ex situ human whole brain perfusion protocol for immunohistochemistry.
- Author
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Hade AC, Philips MA, Promet L, Jagomäe T, Hanumantharaju A, Salumäe L, Reimann E, Plaas M, Vasar E, and Väli M
- Subjects
- Humans, Immunohistochemistry, Cost-Benefit Analysis, Perfusion methods, Fixatives, Brain pathology
- Abstract
Background: Chemical fixation of the brain can be executed through either the immersion method or the perfusion method. Perfusion fixation allows for better preservation of the brain tissue's ultrastructure, as it provides rapid and uniform delivery of the fixative to the tissue. Still, not all facilities have the expertise to perform perfusion fixation, with initial high cost and complexity of perfusion systems as the main factors limiting its widespread usage., New Method: Here we present our low-cost approach of whole brain ex situ perfusion fixation to overcome the aforementioned limitations. Our self-made perfusion system, constructed utilising commercially accessible and affordable medical resources alongside laboratory and everyday items, demonstrates the capability to generate superior histological stainings of brain tissue. The perfused tissue can be stored prior to proceeding with IHC for at least one year., Results: Our method yielded high-quality results in histological stainings using both free-floating cryosections and paraffin-embedded tissue sections. The system is fully reusable and complies with the principles of sustainable management., Comparison With Existing Methods: Our whole brain perfusion system has been assembled from simple components and is able to achieve a linear flow with a pressure of 70 mmHg corresponding to the perfusion pressure of the brain., Conclusions: Our ex situ method can be especially useful in research settings where expensive perfusion systems are not affordable or in any field with high time pressure, making it suitable for the field of forensic medicine or pathology in general., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
36. Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.
- Author
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Jagomäe T, Gaur N, Seppa K, Reimets R, Pastak M, Plaas M, Kaasik A, Vasar E, and Plaas M
- Subjects
- Humans, Rats, Animals, Infant, Incretins pharmacology, Glucagon-Like Peptide 1 pharmacology, Gastric Inhibitory Polypeptide, Wolfram Syndrome drug therapy, Insulin-Secreting Cells
- Abstract
Aim: Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1 , with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS., Methods: Eight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis., Results: DA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats., Conclusion: We present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jagomäe, Gaur, Seppa, Reimets, Pastak, Plaas, Kaasik, Vasar and Plaas.)
- Published
- 2023
- Full Text
- View/download PDF
37. Chitinase dysregulation predicts disease aggressiveness in ALS: Insights from the D50 progression model.
- Author
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Gaur N, Steinbach R, Plaas M, Witte OW, Brill MS, and Grosskreutz J
- Subjects
- Humans, Animals, Motor Neurons, Disease Progression, Aggression, Disease Models, Animal, Amyotrophic Lateral Sclerosis, Chitinases
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2023
- Full Text
- View/download PDF
38. Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome.
- Author
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Punapart M, Reimets R, Seppa K, Kirillov S, Gaur N, Eskla KL, Jagomäe T, Vasar E, and Plaas M
- Subjects
- Rats, Animals, Renin-Angiotensin System genetics, Liraglutide pharmacology, Receptors, Angiotensin metabolism, Calmodulin-Binding Proteins genetics, Membrane Proteins genetics, Membrane Proteins metabolism, Wolfram Syndrome genetics
- Abstract
Biallelic mutations in the gene encoding WFS1 underlie the development of Wolfram syndrome (WS), a rare neurodegenerative disorder with no available cure. We have previously shown that Wfs1 deficiency can impair the functioning of the renin-angiotensin-aldosterone system (RAAS). The expression of two key receptors, angiotensin II receptor type 2 ( Agtr2 ) and bradykinin receptor B1 ( Bdkrb1 ), was downregulated both in vitro and in vivo across multiple organs in a rat model of WS. Here, we show that the expression of key RAAS components is also dysregulated in neural tissue from aged WS rats and that these alterations are not normalized by pharmacological treatments (liraglutide (LIR), 7,8-dihydroxyflavone (7,8-DHF) or their combination). We found that the expression of angiotensin II receptor type 1a ( Agtr1a ), angiotensin II receptor type 1b ( Agtr1b ), Agtr2 and Bdkrb1 was significantly downregulated in the hippocampus of WS animals that experienced chronic experimental stress. Treatment-naïve WS rats displayed different gene expression patterns, underscoring the effect of prolonged experiment-induced stress. Altogether, we posit that Wfs1 deficiency disturbs RAAS functioning under chronic stressful conditions, thereby exacerbating neurodegeneration in WS.
- Published
- 2023
- Full Text
- View/download PDF
39. Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice.
- Author
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Kaare M, Jayaram M, Jagomäe T, Singh K, Kilk K, Mikheim K, Leevik M, Leidmaa E, Varul J, Nõmm H, Rähn K, Visnapuu T, Plaas M, Lilleväli K, Schäfer MKE, Philips MA, and Vasar E
- Abstract
In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 ( NEGR1 ) gene has been consistently linked with both depression and obesity. Although the linkage between NEGR1 and depression is the strongest, evidence also suggests the involvement of NEGR1 in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. Negr1
-/- mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of Negr1-/- mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in Negr1-/- mice, and escitalopram rescued reduced weight of hippocampi in Negr1-/- mice. The current study is the first to show alterations in the brain monoaminergic systems in Negr1 -deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human NEGR1 gene.- Published
- 2022
- Full Text
- View/download PDF
40. Bovine colostrum-derived antibodies against SARS-CoV-2 show great potential to serve as prophylactic agents.
- Author
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Kangro K, Kurašin M, Gildemann K, Sankovski E, Žusinaite E, Lello LS, Pert R, Kavak A, Poikalainen V, Lepasalu L, Kuusk M, Pau R, Piiskop S, Rom S, Oltjer R, Tiirik K, Kogermann K, Plaas M, Tiirats T, Aasmäe B, Plaas M, Mumm K, Krinka D, Talpsep E, Kadaja M, Gerhold JM, Planken A, Tover A, Merits A, Männik A, Ustav M Jr, and Ustav M
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, Antibodies, Neutralizing, Antibodies, Viral, Cattle, Colostrum metabolism, Female, Humans, Pregnancy, Spike Glycoprotein, Coronavirus, COVID-19 prevention & control, SARS-CoV-2
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to impose a serious burden on health systems globally. Despite worldwide vaccination, social distancing and wearing masks, the spread of the virus is ongoing. One of the mechanisms by which neutralizing antibodies (NAbs) block virus entry into cells encompasses interaction inhibition between the cell surface receptor angiotensin-converting enzyme 2 (ACE2) and the spike (S) protein of SARS-CoV-2. SARS-CoV-2-specific NAb development can be induced in the blood of cattle. Pregnant cows produce NAbs upon immunization, and antibodies move into the colostrum immediately before calving. Here, we immunized cows with SARS-CoV-2 S1 receptor binding domain (RBD) protein in proper adjuvant solutions, followed by one boost with SARS-CoV-2 trimeric S protein and purified immunoglobulins from colostrum. We demonstrate that this preparation indeed blocks the interaction between the trimeric S protein and ACE2 in different in vitro assays. Moreover, we describe the formulation of purified immunoglobulin preparation into a nasal spray. When administered to human subjects, the formulation persisted on the nasal mucosa for at least 4 hours, as determined by a clinical study. Therefore, we are presenting a solution that shows great potential to serve as a prophylactic agent against SARS-CoV-2 infection as an additional measure to vaccination and wearing masks. Moreover, our technology allows for rapid and versatile adaptation for preparing prophylactic treatments against other diseases using the defined characteristics of antibody movement into the colostrum., Competing Interests: The use of bovine colostrum as a prophylactic agent against SARS-CoV-2 has been patented (US patent application no 63/160,833) by Mario Plaas, K. Kogermann, E. Žusinaite, T. Tiirats, B. Aasmäe, A. Kavak, V. Poikalainen, L. Lepasalu, S. Piiskop, S. Rom, R. Oltjer, K. Kangro, E. Sankovski, J. M. Gerhold, R. Pert, A. Männik, A. Planken, A. Tover, M. Kurašin, M. Ustav and M. Ustav Jr.
- Published
- 2022
- Full Text
- View/download PDF
41. Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles.
- Author
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Tepp K, Aid-Vanakova J, Puurand M, Timohhina N, Reinsalu L, Tein K, Plaas M, Shevchuk I, Terasmaa A, and Kaambre T
- Abstract
The protein wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. Mutations in Wfs1 gene cause autosomal recessive disorder Wolfram syndrome (WS). The first symptom of the WS is diabetes mellitus, so accurate diagnosis of the disease as WS is often delayed. In this study we aimed to characterize the role of the Wfs1 deficiency on bioenergetics of muscles. Alterations in the bioenergetic profiles of Wfs1-exon-5-knock-out (Wfs1KO) male rats in comparison with their wild-type male littermates were investigated using high-resolution respirometry, and enzyme activity measurements. The changes were followed in oxidative (cardiac and soleus) and glycolytic (rectus femoris and gastrocnemius) muscles. There were substrate-dependent alterations in the oxygen consumption rate in Wfs1KO rat muscles. In soleus muscle, decrease in respiration rate was significant in all the followed pathways. The relatively small alterations in muscle during development of WS, such as increased mitochondrial content and/or increase in the OxPhos-related enzymatic activity could be an adaptive response to changes in the metabolic environment. The significant decrease in the OxPhos capacity is substrate dependent indicating metabolic inflexibility when multiple substrates are available., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)
- Published
- 2022
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- View/download PDF
42. Low cardiac content of long-chain acylcarnitines in TMLHE knockout mice prevents ischaemia-reperfusion-induced mitochondrial and cardiac damage.
- Author
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Liepinsh E, Kuka J, Vilks K, Svalbe B, Stelfa G, Vilskersts R, Sevostjanovs E, Goldins NR, Groma V, Grinberga S, Plaas M, Makrecka-Kuka M, and Dambrova M
- Subjects
- Animals, Ischemia, Male, Mice, Mice, Knockout, Reperfusion, Carnitine analogs & derivatives, Mitochondria, Heart
- Abstract
Increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage by stimulating ROS production. N
6 -trimethyllysine dioxygenase (TMLD) is the first enzyme in the carnitine/acylcarnitine biosynthesis pathway. Inactivation of the TMLHE gene (TMLHE KO) in mice is expected to limit long-chain acylcarnitine synthesis and thus induce a cardio- and mitochondria-protective phenotype. TMLHE gene deletion in male mice lowered acylcarnitine concentrations in blood and cardiac tissues by up to 85% and decreased fatty acid oxidation by 30% but did not affect muscle and heart function in mice. Metabolome profile analysis revealed increased levels of polyunsaturated fatty acids (PUFAs) and a global shift in fatty acid content from saturated to unsaturated lipids. In the risk area of ischemic hearts in TMLHE KO mouse, the OXPHOS-dependent respiration rate and OXPHOS coupling efficiency were fully preserved. Additionally, the decreased long-chain acylcarnitine synthesis rate in TMLHE KO mice prevented ischaemia-reperfusion-induced ROS production in cardiac mitochondria. This was associated with a 39% smaller infarct size in the TMLHE KO mice. The arrest of the acylcarnitine biosynthesis pathway in TMLHE KO mice prevents ischaemia-reperfusion-induced damage in cardiac mitochondria and decreases infarct size. These results confirm that the decreased accumulation of ROS-increasing fatty acid metabolism intermediates prevents mitochondrial and cardiac damage during ischaemia-reperfusion., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
43. Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype.
- Author
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Jagomäe T, Seppa K, Reimets R, Pastak M, Plaas M, Hickey MA, Kukker KG, Moons L, De Groef L, Vasar E, Kaasik A, Terasmaa A, and Plaas M
- Subjects
- Animals, C-Peptide metabolism, Diabetes Mellitus, Experimental complications, Disease Models, Animal, Glucagon-Like Peptide-1 Receptor metabolism, Hearing Loss, Sensorineural complications, Liraglutide pharmacology, Male, Nerve Degeneration complications, Optic Nerve drug effects, Optic Nerve pathology, Optic Nerve ultrastructure, Phenotype, Rats, Visual Pathways drug effects, Wolfram Syndrome complications, Diabetes Mellitus, Experimental drug therapy, Glucagon-Like Peptide-1 Receptor agonists, Hearing Loss, Sensorineural drug therapy, Liraglutide therapeutic use, Nerve Degeneration drug therapy, Visual Pathways pathology, Wolfram Syndrome drug therapy
- Abstract
Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 ( WFS1 ) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.
- Published
- 2021
- Full Text
- View/download PDF
44. The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1 , Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome.
- Author
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Punapart M, Seppa K, Jagomäe T, Liiv M, Reimets R, Kirillov S, Kaasik A, Moons L, De Groef L, Terasmaa A, Vasar E, and Plaas M
- Subjects
- Aldosterone blood, Animals, Cells, Cultured, Disease Models, Animal, Gene Knockout Techniques, Liraglutide pharmacology, Liraglutide therapeutic use, Male, Rats, Renin-Angiotensin System drug effects, Valproic Acid pharmacology, Valproic Acid therapeutic use, Wolfram Syndrome blood, Wolfram Syndrome drug therapy, Calmodulin-Binding Proteins genetics, Down-Regulation drug effects, Membrane Proteins genetics, Receptor, Angiotensin, Type 2 genetics, Receptor, Bradykinin B1 genetics, Wolfram Syndrome genetics
- Abstract
Wolfram syndrome (WS) 1 is a rare monogenic neurodegenerative disorder caused by mutations in the gene encoding WFS1. Knowledge of the pathophysiology of WS is incomplete and to date, there is no treatment available. Here, we describe early deviations in the renin-angiotensin-aldosterone system (RAAS) and bradykinin pathway (kallikrein kinin system, KKS) observed in a rat model of WS ( Wfs1 KO) and the modulative effect of glucagon-like peptide-1 receptor agonist liraglutide (LIR) and anti-epileptic drug valproate (VPA), which have been proven effective in delaying WS progression in WS animal models. We found that the expression of key receptors of the RAAS and KKS, Agtr2 and Bdkrb1 , were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in Wfs1 , KO serum aldosterone levels were substantially decreased and bradykinin levels increased compared to WT animals. Neither treatment nor their combination affected the gene expression levels seen in the Wfs1 KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the Wfs1 KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that Wfs1 deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems.
- Published
- 2021
- Full Text
- View/download PDF
45. High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice.
- Author
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Kaare M, Mikheim K, Lilleväli K, Kilk K, Jagomäe T, Leidmaa E, Piirsalu M, Porosk R, Singh K, Reimets R, Taalberg E, Schäfer MKE, Plaas M, Vasar E, and Philips MA
- Abstract
In the large GWAS studies, NEGR1 gene has been one of the most significant gene loci for body mass phenotype. The purpose of the current study was to clarify the role of NEGR1 in the maintenance of systemic metabolism, including glucose homeostasis, by using both male and female Negr1
-/- mice receiving a standard or high fat diet (HFD). We found that 6 weeks of HFD leads to higher levels of blood glucose in Negr1-/- mice. In the glucose tolerance test, HFD induced phenotype difference only in male mice; Negr1-/- male mice displayed altered glucose tolerance, accompanied with upregulation of circulatory branched-chain amino acids (BCAA). The general metabolomic profile indicates that Negr1-/- mice are biased towards glyconeogenesis, fatty acid synthesis, and higher protein catabolism, all of which are amplified by HFD. Negr1 deficiency appears to induce alterations in the efficiency of energy storage; reduced food intake could be an attempt to compensate for the metabolic challenge present in the Negr1-/- males, particularly during the HFD exposure. Our results suggest that the presence of functional Negr1 allows male mice to consume more HFD and prevents the development of glucose intolerance, liver steatosis, and excessive weight gain.- Published
- 2021
- Full Text
- View/download PDF
46. Age- and airway disease related gene expression patterns of key SARS-CoV-2 entry factors in human nasal epithelia.
- Author
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Plaas M, Seppa K, Gaur N, Kasenõmm P, and Plaas M
- Subjects
- Adolescent, Adult, Age Factors, Aged, Biomarkers, Child, Child, Preschool, Comorbidity, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Virus Internalization, Young Adult, COVID-19 genetics, COVID-19 virology, Gene Expression Regulation, Host-Pathogen Interactions genetics, Nasal Mucosa metabolism, Nasal Mucosa virology, SARS-CoV-2 physiology
- Abstract
The global COVID-19 pandemic caused by SARS-CoV-2 predominantly affects the elderly. Differential expression of SARS-CoV-2 entry genes may underlie the variable susceptibility in different patient groups. Here, we examined the gene expression of key SARS-CoV-2 entry factors in mucosal biopsies to delineate the roles of age and existing chronic airway disease. A significant inverse correlation between ACE2 and age and a downregulation of NRP1 in patients with airway disease were noted. These results indicate that the interplay between various factors may influence susceptibility and the disease course., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
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47. Dopamine System, NMDA Receptor and EGF Family Expressions in Brain Structures of Bl6 and 129Sv Strains Displaying Different Behavioral Adaptation.
- Author
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Varul J, Eskla KL, Piirsalu M, Innos J, Philips MA, Visnapuu T, Plaas M, and Vasar E
- Abstract
C57BL/6NTac (Bl6) and 129S6/SvEvTac (129Sv) mice display different coping strategies in stressful conditions. Our aim was to evaluate biomarkers related to different adaptation strategies in the brain of male 129Sv and Bl6 mice. We focused on signaling pathways related to the dopamine (DA) system, N-methyl-D-aspartate (NMDA) receptor and epidermal growth factor (EGF) family, shown as the key players in behavioral adaptation. Mice from Bl6 and 129Sv lines were divided into either home cage controls (HCC group) or exposed to repeated motility testing and treated with saline for 11 days (RMT group). Distinct stress responses were reflected in severe body weight loss in 129Sv and the increased exploratory behavior in Bl6 mice. Besides that, amphetamine caused significantly stronger motor stimulation in Bl6. Together with the results from gene expression (particularly Maob ), this study supports higher baseline activity of DA system in Bl6. Interestingly, the adaptation is reflected with opposite changes of DA markers in dorsal and ventral striatum. In forebrain, stress increased the gene expressions of Egf-Erbb1 and Nrg1/Nrg2-Erbb4 pathways more clearly in 129Sv, whereas the corresponding proteins were significantly elevated in Bl6. We suggest that not only inhibited activity of the DA system, but also reduced activity of EGF family and NMDA receptor signaling underlies higher susceptibility to stress in 129Sv. Altogether, this study underlines the better suitability of 129Sv for modelling neuropsychiatric disorders than Bl6.
- Published
- 2021
- Full Text
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48. Liraglutide, 7,8-DHF and their co-treatment prevents loss of vision and cognitive decline in a Wolfram syndrome rat model.
- Author
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Seppa K, Jagomäe T, Kukker KG, Reimets R, Pastak M, Vasar E, Terasmaa A, and Plaas M
- Subjects
- Animals, Blindness blood, Blindness physiopathology, Blood Glucose metabolism, Body Weight, Calmodulin-Binding Proteins deficiency, Calmodulin-Binding Proteins metabolism, Cognitive Dysfunction blood, Disease Models, Animal, Disease Progression, Drug Therapy, Combination, Fasting blood, Flavones pharmacology, Gene Expression Regulation drug effects, Gene Knockout Techniques, Glucagon-Like Peptide-1 Receptor agonists, Glucagon-Like Peptide-1 Receptor metabolism, Hippocampus drug effects, Hippocampus metabolism, Hyperglycemia pathology, Learning drug effects, Liraglutide pharmacology, Male, Membrane Proteins deficiency, Membrane Proteins metabolism, Nerve Degeneration complications, Nerve Degeneration pathology, Optic Nerve drug effects, Optic Nerve pathology, Optic Nerve physiopathology, Optic Nerve ultrastructure, Rats, Remyelination, Visual Acuity drug effects, Wolfram Syndrome blood, Blindness drug therapy, Blindness prevention & control, Cognitive Dysfunction drug therapy, Cognitive Dysfunction prevention & control, Flavones therapeutic use, Liraglutide therapeutic use, Wolfram Syndrome drug therapy
- Abstract
Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5-8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.
- Published
- 2021
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49. GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome.
- Author
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Seppa K, Toots M, Reimets R, Jagomäe T, Koppel T, Pallase M, Hasselholt S, Krogsbæk Mikkelsen M, Randel Nyengaard J, Vasar E, Terasmaa A, and Plaas M
- Subjects
- Animals, Apoptosis drug effects, Calmodulin-Binding Proteins deficiency, Calmodulin-Binding Proteins genetics, Disease Models, Animal, Endoplasmic Reticulum Stress drug effects, Glucose Tolerance Test, Hyperglycemia pathology, Hyperglycemia prevention & control, Liraglutide pharmacology, Male, Membrane Proteins deficiency, Membrane Proteins genetics, Neurons physiology, Neuroprotective Agents pharmacology, Optic Nerve metabolism, Rats, Rats, Transgenic, Retinal Ganglion Cells cytology, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells metabolism, Wolfram Syndrome metabolism, Wolfram Syndrome pathology, Glucagon-Like Peptide-1 Receptor agonists, Liraglutide therapeutic use, Neuroprotective Agents therapeutic use, Wolfram Syndrome drug therapy
- Abstract
Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.
- Published
- 2019
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50. Calcium Signaling and Contractility in Cardiac Myocyte of Wolframin Deficient Rats.
- Author
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Cagalinec M, Zahradníková A, Zahradníková A Jr, Kováčová D, Paulis L, Kureková S, Hot'ka M, Pavelková J, Plaas M, Novotová M, and Zahradník I
- Abstract
Wolframin (Wfs1) is a membrane protein of the sarco/endoplasmic reticulum. Wfs1 mutations are responsible for the Wolfram syndrome, characterized by diabetic and neurological symptoms. Although Wfs1 is expressed in cardiac muscle, its role in this tissue is not clear. We have characterized the effect of invalidation of Wfs1 on calcium signaling-related processes in isolated ventricular myocytes of exon5-Wfs1 deficient rats (Wfs1
-e5/-e5 ) before the onset of overt disease. Calcium transients and contraction were measured in field-stimulated isolated myocytes using confocal microscopy with calcium indicator fluo-3 AM and sarcomere length detection. Calcium currents and their calcium release-dependent inactivation were characterized in whole-cell patch-clamp experiments. At 4 months, Wfs1-e5/-e5 animals were euglycemic, and echocardiographic examination revealed fully compensated cardiac function. In field-stimulated isolated ventricular myocytes, both the amplitude and the duration of contraction of Wfs1-e5/-e5 animals were elevated relative to control Wfs1+/+ littermates. Increased contractility of myocytes resulted largely from prolonged cytosolic calcium transients. Neither the amplitude of calcium currents nor their voltage dependence of activation differed between the two groups. Calcium currents in Wfs1-e5/-e5 myocytes showed a larger extent of inactivation by short voltage prepulses applied to selectively induce calcium release-dependent inactivation of calcium current. Neither the calcium content of the sarcoplasmic reticulum, measured by application of 20 mmol/l caffeine, nor the expression of SERCA2, determined from Western blots, differed significantly in myocytes of Wfs1-e5/-e5 animals compared to control ones. These experiments point to increased duration of calcium release in ventricular myocytes of Wfs1-e5/-e5 animals. We speculate that the lack of functional wolframin might cause changes leading to upregulation of RyR2 channels resulting in prolongation of channel openings and/or a delay in termination of calcium release.- Published
- 2019
- Full Text
- View/download PDF
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