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| 2. |
- Ceder, Mikaela M., et al.
(författare)
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Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster
- 2020
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Many newly identified solute carriers (SLCs) and putative transporters have the possibility to be intricately involved in glucose metabolism. Here we show that many transporters of this type display a high degree of regulation at both mRNA and protein level following no or low glucose availability in mouse cortex cultures. We show that this is also the case in Drosophila melanogaster subjected to starvation or diets with different sugar content. Interestingly, re-introduction of glucose to media, or refeeding flies, normalized the gene expression of a number of the targets, indicating a fast and highly dynamic control. Our findings demonstrate high conservation of these transporters and how dependent both cell cultures and organisms are on gene and protein regulation during metabolic fluctuations. Several transporter genes were regulated simultaneously maybe to initiate alternative metabolic pathways as a response to low glucose levels, both in the cell cultures and in D. melanogaster. Our results display that newly identified SLCs of Major Facilitator Superfamily type, as well as the putative transporters included in our study, are regulated by glucose availability and could be involved in several cellular aspects dependent of glucose and/or its metabolites. Recently, a correlation between dysregulation of glucose in the central nervous system and numerous diseases such as obesity, type 2 diabetes mellitus as well as neurological disease such as Alzheimer’s and Parkinson’s diseases indicate a complex regulation and fine tuning of glucose levels in the brain. The fact that almost one third of transporters and transporter-related proteins remain orphans with unknown or contradictive substrate profile, location and function, pinpoint the need for further research about them to fully understand their mechanistic role and their impact on cellular metabolism.
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| 3. |
- Filipsson, Helena L., et al.
(författare)
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Geochemical composition of Baltic benthic foraminifera collected and cultured over a large salinity gradient.
- 2017
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Konferensbidrag (refereegranskat)abstract
- Some of the most significant challenges in paleoclimate research arise from the need to both understand and reduce the uncertainty associated with proxies for climate reconstructions. These challenges were further highlighted in connection with the IODP Exp.347 Baltic Sea Paleoenvironment. We have investigated temperature and salinity proxies through a combination of field-and culture-based benthic foraminiferal samplesfrom the Baltic(sal. 14)-Kattegat(sal. 32), together with genetic characterization. Two long-term experiments at twotemperatures and three salinities were performed. We present foraminiferal assemblage,trace element (Mg/Ca, Ba/Ca, Mn/Ca),and stable O and C isotope results from these locations, including LA-ICP-MS data from cultured specimens. Furthermore, specimens of Elphidium and Ammonia were genetically characterized; the results indicate that the same genetic type of Elphidiumis found in both salinity regimes, but that the Ammoniagenetic types differ depending on the prevailing salinity regime.
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| 4. |
- Groeneveld, Jeroen, et al.
(författare)
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Assessing proxy signatures of temperature, salinity, and hypoxia in the Baltic Sea through foraminifera-based geochemistry and faunal assemblages
- 2018
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Ingår i: Journal of Micropalaeontology. - : Copernicus GmbH. - 0262-821X .- 2041-4978. ; 37:2, s. 403-429
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Tidskriftsartikel (refereegranskat)abstract
- Current climate and environmental changes strongly affect shallow marine and coastal areas like the Baltic Sea. This has created a need for a context to understand the severity and potential outcomes of such changes. The context can be derived from paleoenvironmental records during periods when comparable events happened in the past. In this study, we explore how varying bottom water conditions across a large hydrographic gradient in the Baltic Sea affect benthic foraminiferal faunal assemblages and the geochemical composition of their calcite tests. We have conducted both morphological and molecular analyses of the faunas and we evaluate how the chemical signatures of the bottom waters are recorded in the tests of several species of benthic foraminifera. We focus on two locations, one in the Kattegat (western Baltic Sea) and one in Hanö Bay (southern Baltic Sea). We show that seawater Mn-•Ca, Mg-•Ca, and Ba-•Ca (Mn-•Casw, Mg-•Casw, and Ba-•Casw) variations are mainly controlled by dissolved oxygen concentration and salinity. Their respective imprints on the foraminiferal calcite demonstrate the potential of Mn-•Ca as a proxy for hypoxic conditions, and Ba-•Ca as a proxy for salinity in enclosed basins such as the Baltic Sea. The traditional use of Mg-•Ca as a proxy to reconstruct past seawater temperatures is not recommended in the region, as it may be overprinted by the large variations in salinity (specifically on Bulimina marginata), Mg-•Casw, and possibly also the carbonate system. Salinity is the main factor controlling the faunal assemblages: a much more diverse fauna occurs in the higher-salinity (- 32) Kattegat than in the low-salinity (- 15) Hanö Bay. Molecular identification shows that only Elphidium clavatum occurs at both locations, but other genetic types of both genera Elphidium and Ammonia are restricted to either low- or high-salinity locations. The combination of foraminiferal geochemistry and environmental parameters demonstrates that in a highly variable setting like the Baltic Sea, it is possible to separate different environmental impacts on the foraminiferal assemblages and therefore use Mn-•Ca, Mg-•Ca, and Ba-•Ca to reconstruct how specific conditions may have varied in the past.
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| 6. |
- Mätlik, Kärt, et al.
(författare)
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Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578.
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Tidskriftsartikel (refereegranskat)abstract
- Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.
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| 7. |
- Nordenankar, Karin, et al.
(författare)
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Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity
- 2015
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Ingår i: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 220:4, s. 2171-2190
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Tidskriftsartikel (refereegranskat)abstract
- Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.
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| 8. |
- Perland, Emelie, et al.
(författare)
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Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Out of the 430 known solute carriers (SLC) in humans, 30% are still orphan transporters regarding structure, distribution or function. Approximately one third of all SLCs belong to the evolutionary conserved and functionally diverse Major Facilitator Superfamily (MFS). Here, we studied the orphan proteins, MFSD4A and MFSD9, which are atypical SLCs of MFS type. Hidden Markov Models were used to identify orthologues in several vertebrates, and human MFSD4A and MFSD9 share high sequence identity with their identified orthologues. MFSD4A and MFSD9 also shared more than 20% sequence identity with other phylogenetically related SLC and MFSD proteins, allowing new family clustering. Homology models displayed 12 transmembrane segments for both proteins, which were predicted to fold into a transporter-shaped structure. Furthermore, we analysed the location of MFSD4A and MFSD9 in adult mouse brain using immunohistochemistry, showing abundant neuronal protein staining. As MFSD4A and MFSD9 are plausible transporters expressed in food regulatory brain areas, we monitored transcriptional changes in several mouse brain areas after 24 hours food-deprivation and eight weeks of high-fat diet, showing that both genes were affected by altered food intake in vivo. In conclusion, we propose MFSD4A and MFSD9 to be novel transporters, belonging to disparate SLC families. Both proteins were located to neurons in mouse brain, and their mRNA expression levels were affected by the diet.
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| 10. |
- Rajagopalan, Aparna, et al.
(författare)
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Reduced Gene Expression Levels of Munc13-1 and Additional Components of the Presynaptic Exocytosis Machinery Upon Conditional Targeting of Vglut2 in the Adolescent Mouse
- 2014
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 68:12, s. 624-633
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Tidskriftsartikel (refereegranskat)abstract
- Presynaptic proteins orchestrate an intricate interplay of dynamic interactions in order to regulate quantal exocytosis of transmitter-filled vesicles, and their dysregulation might cause neurological and neuropsychiatric dysfunction. Mice carrying a spatiotemporal restriction in the expression of the Vesicular glutamate transporter 2 (Vglut2; aka Slc17a6) in the cortex, amygdala and hippocampal subiculum from the third postnatal week show a strong anxiolytic phenotype and certain behavioral correlates of schizophrenia. To further understand the molecular consequences of this targeted deletion of Vglut2, we performed an unbiased microarray analysis comparing gene expression levels in the subiculum of these conditional Vglut2 knockout mice (Vglut2(f/f;CamKII) cKO) to those in control littermates. Expression of Unc13C (Munc13-3), a member of the Unc/Munc family, previously shown to be important for glutamatergic transmission, was identified to be significantly down-regulated. Subsequent analysis by quantitative RT-PCR revealed a 50% down-regulation of Munc 13-1, the gene encoding the Unc/Munc subtype described as an essential component in the majority of glutamtergic synapses in the hippocampus. Genes encoding additional components of the presynaptic machinery were also found regulated, including Rab3A, RIM1, as well as Syntaxin1 and Synaptobrevin. Altered expression levels of these genes were further found in the amygdala and in the retrosplenial group of the cortex, additional regions in which Vglut2 was conditionally targeted. These findings suggest that expression levels of Vglut2 might be important for the maintenance of gene expression in the presynaptic machinery in the adult mouse brain. Synapse 68:624-633, 2014.
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