Voditeljica:
prof. dr. sc. Svjetlana Kalanj Bognar, dr. med.
Istraživački tim:
dr. sc. Kristina Mlinac (postdoktorant),
Katarina Ilić, dr. med. (doktorand)
Suradnici:
dr. sc. Željka Vukelić,
dr. sc. Dragana Fabris,
dr. sc. Marija Heffer, dr. med. (Medicinski fakultet Osijek),
dr. sc. Koraljka Bačić Baronica,
dr. med. (neurolog, Odjel neurologije, Klinička bolnica “Sveti Duh”, Zagreb)
Dugoročni ciljevi naše grupe su istražiti:
ulogu membranskih lipida u razvoju središnjeg živčanog sustava i u neurodegenerativnim procesima.
utjecaj promjena sastava i strukture lipida na ekspresiju i specifičnu funkciju membranskih proteina.
ulogu specifičnih interakcija između membranskih lipida i proteina u organizaciji sinaptičke membrane.
Područje za koje smo posebno zainteresirani su membranski glikosfingolipidi/gangliozidi kojih se u izobilju mogu naći u središnjem živčanom sustavu sisavaca. Gangliozidi nisu ravnomjerno raspoređeni kroz staničnu membranu neurona, već koncentrirani u lipidnim nakupinama unutar membrane aksona gdje su uključeni u specifične interakcije s molekulama ekstracelularnog matriksa. Do sada je u životinjskim stanicama pokazano da gangliozidi imaju brojne uloge: uključeni su u proliferaciju, diferencijaciju stanica, apoptozu, prijenos signala, adheziju stanica i međustaničnu komunikaciju. Gangliozidi u središnjem živčanom sustavu omogućuju odgovarajuće interakcije aksona i glija stanica, te također sudjeluju u molekularnim mehanizmima učenja i pamćenja. Rezultati naših istraživanja dosad su pokazali određene promjene u količini i sastavu gangliozida u moždanom tkivu bolesnika s Alzheimerovom bolešću, kao i povećanu aktivnost lizosomalnih enzima uključenih u razgradnju sfingolipida u ekstraneuralnim stanicama (leukociti, kožni fibroblasti) u pacijenata s Alzheimerovom bolešću. Naši rezultati, zajedno s rezultatima ostalih skupina, potvrđuju da su promjene u koncentraciji, sastavu i metabolizmu, a posebno razgradnja glikosfingolipida, doprinosi složenoj patogenezi neurodegeneracije.
Naša posljednja istraživanja usmjerena su na analizu učinka promjene u sastavu i strukturi membranskih lipida na ekspresiju i specifičnu funkciju membranskih proteina u središnjem živčanom sustavu sisavaca. Lipidni okoliš i interakcije lipida i proteina unutar membrane su od ključne važnosti za pravilno pozicioniranje i funkciju membranskih proteina te stoga iznimno važni za organizaciju sinaptičkih membrana. Naši rezultati pokazuju da su u moždanom tkivu miša s promijenjenom biosintezom proteina (mišji model knocked out gena za diferencijaciju enzima za biosintezu gangliozida) prisutne različite modifikacije strukture gangliozida koje još nisu opisane u tkivu miša divljeg tipa, a mogu ulaziti u interakcije s drugim membranskim molekulama. Također smo uočili značajne promjene u ekspresiji gena i proteina na istim mišjim modelima. Promjene u ekspresiji su najistaknutije za gene koji kodiraju membranske proteine i koji su uključeni u interakcije s drugim proteinima. Od niza gena s promijenjenom ekspresijom posebno nas je zainteresirao gen za neuroplastin zbog poznatih ulogama neuroplastina u živčanom sustavu.
Neuroplastin je transmembranski protein koji pripada staničnim adhezijskim molekulama i uključen je u sinaptičku plastičnost te modulaciju neuritogeneze. Opisana je vrlo specifična raspodjela neuroplastina u središnjem živčanom sustavu, osobito u mozgu glodavaca. Međutim, lokalizacija i uloga neuroplastina u ljudskom mozgu nije sustavno istražena. Stoga je jedan od ciljeva naše grupe sistematično ispitati ekspresiju neuroplastina u ljudskom mozgu. Osim toga, cilj nam je potvrditi našu hipotezu na temelju preliminarnih rezultata koji pokazuju da je neuroplastin uključen u sinaptičku plastičnost tijekom kritičnih faza razvoja ljudskog mozga kao i u neurodegenerativnim procesima.
Projekti:
Uloga membranskih lipida u moždanom razvoju, starenju i neurodegeneraciji (MZOS, 2007.-2014., PI: S. Kalanj Bognar)
Neuroplastin i gangliozidi u organizaciji sinaptičke membrane (Hrvatsko-Njemački bilateralni projekt, 2014., PI: K. Mlinac)
Ekspresija neuroplastina u ljudskom hipokampusu (projekt financiran od strane Sveučilišta u Zagrebu, 2014., PI: S. Kalanj Bognar)
Međunarodna suradnja:
Leibniz Institute for Neurobiology, Magdeburg, Germany - dr. Rodrigo Herrera Molina, dr. Karl-Heinz Smalla, dr. Dirk Montag
Head:
Associate Professor Svjetlana Kalanj Bognar; MD, PhD
Team:
Kristina Mlinac, PhD (postdoctoral researcher);
Katarina Ilić, MD (PhD student)
Collaborators:
Željka Vukelić, PhD;
Dragana Fabris, PhD;
Marija Heffer, MD, PhD (School of Medicine University of Osijek),
Koraljka Bačić Baronica, MD, PhD (neurologist; Department of Neurology, Clinical Hospital “Sveti Duh”, Zagreb)
Long-term interests of our group are to investigate:
The role of membrane lipids in the central nervous system development and neurodegeneration
The influence of changes in lipid composition and structure on the expression and specific functions of membrane proteins
The role of specific interactions between membrane lipids and membrane proteins in the organization of synaptic membrane.
We are particularly interested in membrane glycosphingolipids/gangliosides which are especially abundant in mammalian central nervous system. Gangliosides are not evenly distributed throughout the membrane, but rather more concentrated in lipid rafts within axonal membranes where they engage in specific interactions with molecules in the extracellular matrix. Gangliosides have numerous roles in animal cells: they are involved in proliferation, differentiation, apoptosis, signal transduction, cell adhesion and intercellular communication. Gangliosides in the nervous system enable proper axon-glia interactions, as well as participate in the molecular mechanism of learning and memory. The results of our studies so far showed the specific changes in quantity and composition of gangliosides in brain tissue of patients with Alzheimer’s disease, as well as increased activity of lysosomal enzymes involved in the breakdown of sphingolipids in extraneural cells (leukocytes, skin fibroblasts) of patients with Alzheimer’s disease. Our results, in conjunction with the results of other groups, confirm that changes in concentration, composition and metabolism, especially degradation of glycosphingolipids, contribute to complex pathogenesis of neurodegeneration.
Our recent research is focused on the analysis of the effect of changes in membrane lipid composition and structure on the expression and specific functions of membrane proteins in mammalian central nervous system. Lipid environment and lipid-protein interactions within the membrane are crucial for proper positioning and function of membrane proteins and therefore exceptionally important for the organization of synaptic membranes. Our results show that in brain tissue of mice with altered ganglioside biosynthesis (mouse models with knocked out genes for different ganglioside biosynthetic enzymes) different modifications of ganglioside structures are present not yet described in tissue of wild-type mice which can influence the interactions with other membrane molecules. We also observed significant changes in gene and protein expression in the same mouse models, the changes in expression being most prominent for genes coding for membrane proteins involved in interactions with other proteins. From the array of genes with differential expression, we became especially interested in neuroplastin due to known roles of neuroplastin in the nervous system.
Neuroplastin is a transmembrane protein belonging to cell adhesion molecules and it is involved in synaptic plasticity and modulation of neuritogenesis. A very specific distribution of neuroplastin in the central nervous system has been described, especially in rodent brain. However, the localization and roles of neuroplastin in human brain have not been systematically investigated. Therefore, one of the goals of our group is to systematically examine the expression of neuroplastin in human brain. Additionally, we aim to confirm our hypothesis based on preliminary results that neuroplastin is involved in synaptic plasticity in critical phases in human brain development as well as in neurodegeneration.
Projects:
The role of membrane lipids in brain development, aging and neurodegeneration (MZOS, 2007.-2014., PI: S. Kalanj Bognar)
Neuroplastin and gangliosides in organization of synaptic membrane (Croatian-German bilateral project, 2014., PI: K. Mlinac)
Expression of neuroplastin in human hippocampus (project financed by the University of Zagreb, 2014., PI: S. Kalanj Bognar)
International collaboration:
Leibniz Institute for Neurobiology, Magdeburg, Germany - dr. Rodrigo Herrera Molina, dr. Karl-Heinz Smalla, dr. Dirk Montag
- Bačić Baronica K, Mlinac K et al: Progression of multiple sclerosis is associated with gender differences in glutathione S-transferase P1 detoxification pathway. Acta Neurobiol Exp, 74(3):257-265, 2014.
- Mlinac K, Fabris D, Vukelić Ž, Rožman M, Heffer M, Kalanj Bognar S: Structural analysis of brain ganglioside acetylation patterns in mice with altered ganglioside biosynthesis. Carbohydrate Res, 382:1-8, 2013.
- Mlinac K, Jovanov Milošević N, Heffer M, Smalla KH, Schnaar RL, Kalanj Bognar S: Neuroplastin Expression in the Hippocampus of Mice Lacking Complex Gangliosides. J Mol Neurosci. 48(1);161-166, 2012.
- Mlinac Kristina, Fon Tacer K, Heffer M, Rozman D, Kalanj Bognar S: Cholesterogenic genes expression in brain and liver of ganglioside-deficient mice. Molecular and cellular biochemistry, 369(1/2):127-133, 2012.
- Mlinac K and Kalanj Bognar S: Role of gangliosides in brain aging and neurodegeneration. Translational Neuroscience, 1(4):300-307, 2010.
- Vukelić Ž, Bognar SK, Froesch M, et al: Human gliosarcoma-associated ganglioside composition is complex and distinctive as evidenced by high-performance mass spectrometric determination and structural characterization.Glycobiology 17(5):504-15, 2007.
- Kalanj Bognar S: Ganglioside catabolism is altered in fibroblasts and leukocytes from Alzheimer's disease patients. Neurobiol Aging. 27(9):1354-6, Sep 2006.
- Kalanj Bognar S et al: Leukocyte Lysosomal Enzymes in Alzheimer's Disease and Down's Syndrome. J Gerontol A Biol Sci Med Sci 57A (1):B16-B21, 2002.
- Vukelić Ž and Kalanj Bognar S: Cell density-dependent changes of glycosphingolipid biosynthesis in cultured human skin fibroblasts. Glycoconjugate J, 18:429-437, 2001
- Kračun I, Kalanj S, Talan-Hranilović J, Ćosović Č: Cortical distribution of gangliosides in Alzheimer's disease. Neurochem Int 20, 3:433-438, 1992.
