The International Institute
of Molecular Mechanisms and Machines
Polish Academy of Sciences
Justyna Zmorzyńska, PhD
Group Leader
Laboratory of Developmental Neurobiology
RESEARCH INTERESTS
The lab focuses on early development of brain connectivity in the context of neuropsychiatric diseases such as autism spectrum disorder or anxiety disorder. We seek mechanistic understanding of variable expressivity of neuropsychiatric phenotypes. Patients suffering from various genetic diseases present variable neuropsychiatric symptoms which often do not correlate with mutation burden. We explore molecular and cellular mechanisms that may regulate this variability using high-throuput methodologies.
We demonstrated that commissural thinning results in the aberrant regulation of anxiety in the zebrafish model of Tuberous Sclerosis Complex (TSC) which provided a mechanistic link between brain anatomy and human TSC-associated neuropsychiatric disorders (TANDs). On top of this, we identified two potential drug targets for particular aspects of TSC – namely ethosuximide for seizures and ANA-12 for seizures and anxiety. TSC is a rare genetic disease that manifests with early symptoms including mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) hyperactivation, cortical malformations, childhood epilepsy, and TANDs. It is caused by mutations in genes encoding for TSC1 or TSC2. We found that lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions and observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. With live imaging of the developing brain, we showed that lack of Tsc2 delayed axonal development and caused aberrant tract fasciculation. This corresponded with the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in non-motor seizures seen by multiple behavioural analyses and live imaging of the brain activity. The Tsc2-deficient zebrafish also exhibited increased anxiety-like behaviour in the open field test or sudden light changes test and had elevated cortisol levels. Both seizures and anxiety could be rescued by reducing tyrosine receptor kinase B (TrkB) signaling identifying novel potential drug target. We also found that the lack of light-preference behaviour in the Tsc2-deficient zebrafish (otherwise exhibiting increased anxiety-like behaviours and elevated cortisol levels) is caused by impaired sensory integration in the left dorsal habenula due to hyperactive mTorC1.
The lab further explores how TrkB pathway interacts with hyperactivated mTORC1 pathway and tries to indentify the intermediate components that could serve as drug targets for future therapies for neurophychiatric disorders.
PUBLICATIONS
2024
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O Doszyn*, T Dulski*, J Zmorzynska. Diving into the zebrafish brain: exploring neuroscience frontiers with genetic tools, imaging techniques, and behavioral insights. Frontiers in Molecular Neuroscience, 2024, March 12; Volume 17, 10.3389/fnmol.2024.1358844 (*equal contribution)
2023
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O Doszyn, T Dulski, J Zmorzynska. The zebrafish model of Tuberous Sclerosis Complex to study epilepsy in the Handbook of Animal Models in Neurological Disease edited by Colin Martin, Vinood B Patel and Victor R Preedy, Elsevier, 2023.
2022
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Olga Doszyn, Magdalena Kedra, Justyna Zmorzynska. mTORC1 hyperactivation causes sensory integration deficits due to habenula impairment. doi.org/10.1101/2022.07.20.500762, biorxiv, 2022.
2021
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MT Prentzell*, U Rehbein*, MC Sandoval*, A De Meulemeester*, R Baumeister, L Brohée, B Berdel, M Bockwoldt, B Carroll, SR Chowdhury, A von Deimling, C Demetriades, G Figlia, Genomics England Research Consortium, M Eca, G de Araujo, AM Heberle, I Heiland, B Holzwarth, LA Huber, J Jaworski, M Kedra, K Kern, A Kopach, VI Korolchuk, I van 't Land-Kuper, M Macias, M Nellist, W Palm, S Pusch, JM Ramos Pitto, M Reil, A Reintjes, F Reuter, JR Sampson, C Scheldeman, A Siekierska, E Stefan, A Teleman, LE Thomas, O Torres-Quesada, S Trump, HD West, P de Witte, S Woltering, T Yordanov, J Zmorzynska, CA Opitz, K Thedieck. The G3BP proteins tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell, 2021, Feb 4; 184(3):655-674. (*equal contribution).
2020
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M Kedra, K Kisielewska, K Banasiak, L Wolinska-Niziol, J Jaworski, J Zmorzynska. TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in a zebrafish model of Tuberous Sclerosis Complex. Proc Natl Acad Sci (PNAS). 2020 Jan 28;117(4):2170-2179.
2018
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Koscielny A, Malik AR, Liszewska E, Zmorzynska J, Tempes A, Tarkowski B, Jaworski J. Adaptor Complex 2 Controls Dendrite Morphology via mTOR-Dependent Expression of GluA2. Molecular Neurobiology, 2018, Feb; 55(2):1590-1606.
2017
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K Switon, K Kotulska, A Janusz-Kaminska, J Zmorzynska, J Jaworski. Molecular neurobiology of mTOR. Neuroscience, 2017, Jan 26; 341:112-153.
2016
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K Switon, K Kotulska, A Janusz-Kaminska, J Zmorzynska, J Jaworski. Tuberous Sclerosis Complex: From Molecular Biology to Novel Therapeutic Approaches. IUBMB Life, 2016 Dec; 68(12):955-962.
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Smeets CJ, Zmorzyńska J, Melo MN, Stargardt A, Dooley C, Bakalkin G, McLaughlin J, Sinke RJ, Marrink SJ, Reits E, Verbeek DS. Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23. Human Molecular Genetics, 2016 Jul 1;25(13):2728-2737.
2015
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C Smeets*, J Jezierska*, H Watanabe, A Duarri, MR Fokkens, M Meijer, Q Zhou, T Yakovleva, E Boddeke, W den Dunnen, J van Deursen, G Bakalkin, HH Kampinga, B van de Sluis, DS Verbeek. Elevated mutant dynorphin A causes Purkinje cell loss and motor dysfunction in spinocerebellar ataxia type 23. Brain. 2015 Sep; 138(Pt 9):2537-52. (*equal contribution)
2014
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J Jezierska, J Goedhart, HH Kampinga, EA Reits, DS Verbeek. SCA14 mutation V138E leads to partly unfolded PKCγ associated with an exposed C-terminus, altered kinetics, phosphorylation and enhanced insolubilization. Journal of Neurochemistry, 2014 Mar;128(5):741-51.
2013
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J Jezierska, G Stevanin, H Watanabe, MR Fokkens, F Zagnoli, J Kok, J Goas, P Bertrand, C Robin, A Brice, G Bakalkin, A Durr, DS Verbeek. Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases. Journal of Neurology, 2013; Vol. 260, Issue 7:1807-1812.
2012
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A Duarri, J Jezierska, MR Fokkens, M Meijer, HJ Schelhaas, WFA den Dunnen, F van Dijk, C Verschuuren-Bemelmans, G Hageman, P van de Vlies, B Küsters, BP van de Warrenburg, B Kremer, C Wijmenga, RJ Sinke, MA Swertz, HH Kampinga, E Boddeke, DS Verbeek. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Annals of Neurololy, 2012 Dec; 72(6):870-80.
2010
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G Bakalkin, H Watanabe*, J Jezierska*, C Depoorter, C Verschuuren-Bemelmans, I Bazov, KA Artemenko, T Yakovleva, D Dooijes, BPC Van de Warrenburg, RA Zubarev, B Kremer, PE Knapp, KF Hauser, C Wijmenga, F Nyberg, RJ Sinke, DS Verbeek. Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. American Journal of Human Genetics, 87(5), 593-603, Nov 12, 2010. (*equal contribution)
ABOUT GROUP LEADER
AWARDS AND FELLOWSHIPS
Award of the 2nd Department of Biological and Agricultural Sciences of the Polish Academy of Sciences in 2020 for the scientific team of the IIMCB composed of: prof. J. Jaworski, M. Kedra, B. Tarkowski, M. Urbanska, and J. Zmorzynska for the series of publications on „New molecular mechanisms of mTORopathy and epilepsy”
Distinction in Konorski award for the best publication for 2020 year. The Jerzy Konorski award is given every year for the best work in the field of neurobiology done in Poland and is awarded by the Polish Neuroscience Society and the Committee of Neurobiology of the Polish Academy of Sciences.
Scholarship of the Minister of Science and Higher Education for Outstanding Young Scientists, Poland. In 2016, a 4-year-long scholarship from the Minister of Science and Higher Education for outstanding young scientists. It is an award for scientific and research achievements. There were only 200 such scholarships granted each year for the whole country.
START II (edition 2016) from Foundation for Polish Science (FNP), Poland, for the outstanding achievements in their field. The prize is awarded a maximum of two times and getting it two times in a row is a great distiction. The START fellowship serves as recognition of the scientific attainments by the young researchers and as an incentive for further growth by enabling them to devote themselves fully to their research.
START (edition 2015) from Foundation for Polish Science (FNP), Poland, for the outstanding achievements in their field. The START fellowship is a personal award and serves as recognition of the scientific attainments by the young scholars and as an incentive for further growth by enabling them to devote themselves fully to their research.
Justyna Zmorzynska is a head of The Laboratory of Developmental Neurobiology. She graduated from University of Warsaw with a MSc degree in Molecular Biology performing her Master project in the Department of Medical Genetics in the Institute of Mother and Child (Warsaw, PL). She did her PhD projects in the Department of Genetics, University Medical Center Groningen in Netherlands. She was awarded the Jan Kornelius de Cock stichting, grants for PhD students, three years in a row (2011-2013). She was a post-doctoral fellow and then senior researcher in the Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw (PL). She did internships in in prof. Didier Stainier lab (Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany) and in Prof. William Harris lab (Department of Physiology, Development and Neuroscience, Cambridge, UK). She is also a founder and a scientific consultant of PIXEL-ANALYSIS, an SME that deals with automated solutions for image analysis. She was a project leader of a SONATA grant and then an OPUS grant. In December 2023, she became a group leader at the IMol PAS.
FUNDING
2021-2024
OPUS19 grant from National Science Centre. Rac1 contribution to brain connectivity impairments and neuropsychiatric disorders in Tuberous Sclerosis Complex (2020/37/B/NZ3/02345; 2,251,260 PLN).
2016-2019
SONATA9 grant from National Science Centre. The role of Zebrafish mTOR in neuronal development in vivo as a key regulator of neuronal circuit formation (2015/17/D/NZ3/03735; 689,000 PLN).
2013
JK de Cock Stichting 2013, a one-year-long research grant for PhD students, for NMDAR interaction with DynA in Spinocerebellar ataxia type 23 (27 000 EUR), NL. It is a great distinction to get it three times in a row.
2012
Travel Grant for Ataxia Research Conference 2012 (Simonsfonds), NL.
JK de Cock Stichting 2012 for Expression study of mouse model of Spinocerebellar ataxia type 23 (60 000 EUR), NL.
2011
Travel Grant for 5th Molecular mechanisms of Neurodegeneration meeting 2011 (Simonsfonds), NL.
JK de Cock Stichting 2011 for Development of a fruit fly model of Spinocerebellar ataxia type 23 (36 000 EUR), NL.