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- 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. |
- 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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| 4. |
- Schweizer, Nadine, 1985-
(författare)
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Across Borders : A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.
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