Molekulaarse neurobioloogia uurimisrühm
TalTech prioriteetne teadussuund
Klassifikaator (Frascati)
Uurimisrühma juht
Uurimisrühma liige
Doktorant
Võtmesõna
neurotrofiinid
BDNF
bHLH transkriptsioonitegurid
TCF4/E2-2
neuraalse aktiivsusega reguleeritud transkriptsioon
Pitt-Hopkinsi sündroom
skisofreenia
Covid-19
südame- ja kardiovaskulaarsed haigused
Ülevaade
Peamiseks uurimisteemaks on geeniekspressiooni ja signaaliülekande regulatsioon närvisüsteemis ja erinevates haigustes. Uuritakse transkriptsiooni, mRNA ja valkude rakusisese lokalisatsiooni, translatsiooni, posttranslatsiooniliste modifikatsioonide ja signaaliülekande molekulaarseid aluseid. Spetsiifiliselt uuritakse: (1) Molekulaarseid mehhanisme, mis kontrollivad neurotrofiin BDNFi transkriptsiooni ja translatsiooni. (2) Aluselise heeliks-ling-heeliks transkriptsioonifaktori TCF4 funktsioone imetajate ja Drosophila närvisüsteemis ja regulatsiooni häireid Pitt-Hopkinsi sündroomis ja skisofreenias. (3) Erinevate haiguste varajase diagnostika molekulaarseid markereid verest.
Tähtsamad tulemused
2023. aasta kõige olulisemad teadustulemused:• Iseloomustati ajust pärineva neurotroofse teguri (BDNF-i) mRNA mittetransleeritavaid piirkondi, mis kontrollivad selle transleeritavust ja rakusisest paiknemist.• Analüüsiti neurotroofse teguri BDNF-i ja selle retseptorite ekspressioonist erinevate imetajate embrüonaalses ja postnataalses arengus, nii mitteneuraalsetes organsüsteemides kui ka aju erinevates osades.• Näidati, et 2-desoksüglükoos, mis jäljendab vahelduvat paastumist, suurendab neuronite plastilisust endoplasmaatilise retiikulumi stressiga seotud transkriptsiooniteguri ATF4 signaaliraja ja neurotroofse teguri BDNF-i ekspressiooni indutseerimise kaudu ning kutsub esile insuldist taastumise ja Alzheimeri tõve vastupanuvõime.• Töötati välja uudne meetod äsja (de novo) sünteesitud valkude rakutüübispetsiifiliseks märgistamiseks puromütsiini inaktiveerimise teel.• Töötati välja molekulaarselt trükitud polümeeril põhinev elektrokeemiline andur neurotroofse teguri BDNF-i kiireks kvantitatiivseks.
Seotud projektid
Seotud struktuuriüksus
Teadusgrupiga seotud publikatsioonid
- Sirp, A., Shubina, A., Tuvikene, J., Tamberg, L., Kiir, C. S., Kranich, L., Timmusk, T. Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues // Frontiers in Molecular Neuroscience (2022) vol. 15, 2, art. 1033224.
https://doi.org/10.3389/fnmol.2022.1033224 - Esvald, E.-E., Tuvikene, J., Moistus, A., Rannaste, K., Kõomägi, S., Timmusk, T. Differential regulation of the BDNF gene in cortical and hippocampal neurons // Journal of neuroscience (2022) vol. 42, 49, p. 9110-9128.
https://doi.org/10.1523/JNEUROSCI.2535-21.2022 - Pupina, N., Avarlaid, A., Sadam, H., Pihlak, A., Jaago, M., Tuvikene, J., Rähni, A., Planken, A., Planken, M., Kalso, E., Tienari, P.J., Nieminen, J.K., Seppänen, M.R.J., Vaheri, A., Lindholm, D., Sinisalo, J., Pussinen, P., Timmusk, T., Palm, K. Immune response to a conserved enteroviral epitope of the major capsid VP1 protein is associated with lower risk of cardiovascular disease // eBioMedicine (2022) vol. 76, art. 103835, 14 p. : ill.
https://doi.org/10.1016/j.ebiom.2022.103835 - Tuvikene, J., Esvald, E.-E., Rähni, A., Uustalu, K., Zhuravskaya, A., Avarlaid, A., Makeyev, E. V., Timmusk, T. Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons // eLife (2021) vol. 10, art. e65161.
https://doi.org/10.7554/eLife.65161 - Sirp, A., Roots, K., Nurm, K., Tuvikene, J., Sepp, M., Timmusk, T. Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia // The journal of biological chemistry (2021) vol. 297, 6, art. 101381.
https://doi.org/10.1016/j.jbc.2021.101381 - Nurm, K., Sepp, M., Castany-Pladevall, C., Creus-Muncunill, J., Tuvikene, J., Sirp, A., Vihma, H., Blake, D.J., Perez-Navarro, E., Timmusk, T. Isoform-specific reduction of the basic helix-Loop-helix transcription factor TCF4 levels in Huntington's disease // eNeuro (2021) Vol. 8, 5, 53 p. : ill.
https://doi.org/10.1523/ENEURO.0197-21.2021 - Esvald, E. E., Tuvikene, J., Sirp, A., Patil, S., Bramham, C. R., Timmusk, T. CREB family transcription factors are major mediators of BDNF transcriptional autoregulation in cortical neurons // Journal of neuroscience (2020) vol. 40, 7, p. 1405-1426 : ill.
https://doi.org/10.1523/JNEUROSCI.0367-19.2019 - Tamberg, L., Jaago, M., Säälik, K., Sirp, A., Tuvikene, J., Šubina, A., Kiir, C. S., Nurm, K., Sepp, M., Timmusk, T., Palgi, M. Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome // Disease Models & Mechanisms (2020) vol. 13, 7, art. dmm042747, 15 p. : ill.
https://doi.org/10.1242/dmm.042747 - Sadam, H., Pihlak, A., Jaago, M., Pupina, N., Rähni, A., Toots, M., Vaheri, A., Nieminen, J. K., Siuko, M., Tienari, P. J., Palm, K. Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients // EBioMedicine (2021) vol. 64, art. 103211, 8 p.
https://doi.org/10.1016/j.ebiom.2021.103211 - Sirp, A., Leite, K., Tuvikene, J., Nurm, K., Sepp, M., Timmusk, T. The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters // Scientific reports (2020) vol. 10, 1, art. 18424.
https://doi.org/10.1038/s41598-020-75437-3 - Metsla, K., Kirss, S., Laks, K., Sildnik, G., Palgi, M., Palumaa, T., Tõugu, V., Palumaa, P. α-Lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease // Journal of Alzheimer's Disease (2022) vol. 85, 2, p. 715-728.
https://doi.org/10.3233/JAD-215026 - Vanaveski, T., Molchanova, S., Pham, D. D., Schäfer, A., Pajanoja, C., Narvik, J., Srinivasan, V., Urb, M., Koivisto, M., Timmusk, T. et al. PGC-1α signaling increases GABA(A) receptor subunit α2 expression, GABAergic neurotransmission and anxiety-like behavior in mice // Frontiers in Molecular Neuroscience (2021) vol. 14, art. 588230.
https://doi.org/10.3389/fnmol.2021.588230 - Jaago, M., Rähni, A., Pupina, N., Pihlak, A ., Sadam, H., Tuvikene, J., Avarlaid, A., Planken, A., Planken, M., Haring, L., Vasar, E., Bacevic, M., Lambert, F., Kalso, E., Pussinen, P., Tienari, P.J., Vaheri, A., Lindholm, D., Timmusk, T., Ghaemmaghami, A.M., Palm, K. Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naïve individuals // Scientific reports (2022) vol. 12, 1, art. 16817 : ill.
https://doi.org/10.1038/s41598-022-20849-6 - Kim, H., Gao, E. B., Draper, A., Berens, N. C., Vihma, H., Zhang, X.,Higashi-Howard, A., Ritola, K. D., Simon, J. M., Kennedy, A. J., Philpot, B. D. Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression // eLife (2022) vol. 11, art. e72290.
https://doi.org/10.7554/eLife.72290 - Jaago, M., Timmusk, U.S., Timmusk, T., Palm, K. Drastic effects on the microbiome of a young rower engaged in high-endurance exercise after a month usage of a dietary fiber supplement // Frontiers in Nutrition (2021) 8, art. #654008, 11 p. : ill.
https://doi.org/10.3389/fnut.2021.654008 - Vrana, N.E., Palm, K., Lavalle, P. Personalization of medical device interfaces: decreasing implant-related complications by modular coatings and immunoprofiling // Future Science OA (2020) vol. 6, 8, 3 p.
https://doi.org/10.2144/fsoa-2020-0074 - Jaago, M., Pupina, N., Rähni, A., Pihlak, A., Sadam, H., Vrana, N.E., Sinisalo, J., Pussinen, P., Palm, K. Antibody response to oral biofilm is a biomarker for acute coronary syndrome in periodontal disease // Communications biology (2022) vol. 5, 1, art. 205, 10 p. : ill.
https://doi.org/10.1038/s42003-022-03122-4 - Jaanson, K., Pärn, A., Timmusk T. Usage of bacterial artificial chromosomes for studying BDNF gene regulation in primary cultures of cortical neurons and astrocytes // Brain-derived neurotrophic factor (BDNF). New York : Humana Press, 2019. p. 13-25. (Neuromethods ; 143).
https://doi.org/10.1007/7657_2018_10 - Wolthers, K. C.; Susi, P., Jochmans, D., Palm, K. et al. Progress in human picornavirus research : New findings from the AIROPico consortium // Antiviral research (2019) vol. 161, p. 100–107 : ill.
http://dx.doi.org/10.1016/j.antiviral.2018.11.010 - Taal, K., Tuvikene, J., Rullinkov, G., Piirsoo, M., Sepp, M., Neuman, T., Tamme, R., Timmusk, T. Neuralized family member NEURL1 is a ubiquitin ligase for the cGMP-specifc phosphodiesterase 9A // Scientific reports (2019) vol. 9, 1, art. 7104, 12 p. : ill.
https://doi.org/10.1038/s41598-019-43069-x - Urb, M., Anier, K., Matsalu, T., Koppel, I., Timmusk, T. et al. Glucocorticoid receptor stimulation resulting from early life stress affects expression of DNA methyltransferases in rat prefrontal cortex // Journal of molecular neuroscience (2019) vol. 68, p. 99–110 : ill.
https://doi.org/10.1007/s12031-019-01286-z - Sadam, H., Pihlak, A., Kivil, A., Pihelgas, S., Jaago, M., Palm, K. et al. Prostaglandin D2 receptor DP1 antibodies predict vaccine-induced and spontaneous narcolepsy type 1 : large-scale study of antibody profiling // EBioMedicine (2018) vol. 29, p. 47−59.
https://doi.org/10.1016/j.ebiom.2018.01.043 - Anier, K., Urb, M., Kipper, K., Timmusk, T. et al. Cocaine-induced epigenetic DNA modification in mouse addiction-specific and non-specific tissues // Neuropharmacology (2018) vol. 139, p. 13-25.
https://doi.org/10.1016/j.neuropharm.2018.06.036 - Karis, K., Eskla, K.-L., Kaare, M., Täht, K., Tuusov, J., Visnapuu, T., Innos, J., Timmusk, T. et al. Altered expression profile of igLON family of neural cell adhesion molecules in the dorsolateral prefrontal cortex of schizophrenic patients // Frontiers in Molecular Neuroscience (2018) Vol. 11, art. 8.
https://doi.org/10.3389/fnmol.2018.00008 - Koppel, I., Jaanson, K., Klasche, A., Tuvikene, J., Tiirik, T., Pärn, A., Timmusk, T. Dopamine cross‐reacts with adrenoreceptors in cortical astrocytes to induce BDNF expression, CREB signaling and morphological transformation // GLIA (2018) vol. 66, 1, p. 206-216 : ill.
https://doi.org/10.1002/glia.23238 - Terenzio, M., Koley, S., Samra, N., Koppel, I. et al. Locally translated mTOR controls axonal local translation in nerve injury // Science (2018) vol. 359, 6382, p. 1416-1421 : ill.
http://dx.doi.org/10.1126/science.aan1053 - Rozenbaum, M., Rajman, M., Rishal, I., Koppel, I. et al. Translatome regulation in neuronal injury and axon regrowth // eNeuro (2018) vol. 5, 2, art. e0276-17.2018, 15 p. : ill.
http://dx.doi.org/10.1523/ENEURO.0276-17.2018 - Doron-Mandel, E., Koppel, I., Abraham, O., Rishal, I., et al. The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization // The EMBO Journal (2021) vol. 40, 20, art. e107158.
https://doi.org/10.15252/embj.2020107158 - Koppel, I., Fainzilber, M. Omics approaches for subcellular translation studies // Molecular omics (2018) vol. 14, 6, p. 380–388 : ill.
http://dx.doi.org/10.1039/c8mo00172c - Urb, M., Niinep, K., Matsalu, T., Kipper, K., Herodes, K., Zharkovsky, A., Timmusk, T., Anier, K., Kalda, A. The role of DNA methyltransferase activity in cocaine treatment and withdrawal in the nucleus accumbens of mice // Addiction Biology (2020) Vol. 25, 1, art. e12720.
https://doi.org/10.1111/adb.12720 - Lekk, I., Cabrera-Cabrera, F., Turconi, G., Tuvikene, J., Esvald, E.-E., Rähni, A., Casserly, L., Garton, D. R., Andressoo, J.-O., Timmusk, T., Koppel, I. Untranslated regions of brain-derived neurotrophic factor (Bdnf) mRNA control its translatability and subcellular localization // The journal of biological chemistry (2023) vol. 299, 2, art. 102897.
https://doi.org/10.1016/j.jbc.2023.102897 - Pärn, A., Olsen, D., Tuvikene, J., Kaas, M., Borisova, E., Bilgin, M., Elhauge, M.,Vilstrup, J., Madsen, P., Ambrozkiewicz, M.C., Goz, R. U., Timmusk, T., Tarabykin,V., Gustafsen, C., Glerup, S. PCSK9 deficiency alters brain lipid composition without affecting brain development and function // Frontiers in molecular neuroscience (2023) vol. 15, art. 1084633.
https://doi.org/10.3389/fnmol.2022.1084633 - Ayankojo, A. G., Boroznjak, R., Reut, J., Tuvikene, J., Timmusk, T., Syritski, V. Electrochemical sensor based on molecularly imprinted polymer for rapid quantitative detection of brain-derived neurotrophic factor // Sensors and Actuators B: Chemical (2023) Vol. 397, art. 134656.
https://doi.org/10.1016/j.snb.2023.134656 - Габович, Б.Е., Веске, А., Дай, Ф., Колесников, Ю.А. Ассоциация генетического полиморфизма гуанозинтрифосфат циклогидролазы и катехол-O-метилтрансферазы с частотой появления хронической боли после операций // Вестник анестезиологии и реаниматологии (2019) Том 16, 5, c. 5−11.
https://doi.org/10.21292/2078-5658-2019-16-5-5-11 - Kumar, A., Karuppagounder, S. S., Chen, Y., Corona, C., Kawaguchi, R., Cheng, Y., Balkaya, M., Sagdullaev, B. T., Wen, Z., Stuart, C., Tuvikene, J., Timmusk, T. et al. 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience // Neuron (2023) vol. 111, 18, p. 2831-2846 : ill.
https://doi.org/10.1016/j.neuron.2023.06.013 - Esvald, E-E., Tuvikene, J., Kiir, C. S., Avarlaid, A., Tamberg, L., Sirp, A., Shubina, A., Cabrera-Cabrera, F., Pihlak, A., Koppel, I., Palm, K., Timmusk, T. Revisiting the expression of BDNF and its receptors in mammalian development // Frontiers in Molecular Neuroscience (2023) vol. 16, art. 1182499.
https://doi.org/10.3389/fnmol.2023.1182499 - Rähni, A., Jaago, M., Sadam, H., Pupina, N., Pihlak, A., Tuvikene, J., Annuk, M.,Mägi, A., Timmusk, T., Ghaemmaghami, A.M., Palm, K. Melanoma-specific antigen-associated antitumor antibody reactivity as an immune-related biomarker for targeted immunotherapies // Communications medicine (2022) vol. 2, 48, 11 p. : ill.
https://doi.org/10.1038/s43856-022-00114-7 - Cabrera-Cabrera, F., Tull, H., Capuana, R., Kasvandik, S., Timmusk, T., Koppel, I. Cell type-specific labelling of newly synthesized proteins by puromycin inactivation // Journal of biological chemistry (2023) vol. 299, 9, art. 105129.
https://doi.org/10.1016/j.jbc.2023.105129