Andrii Domanskyi Team

Contact information

Andrii Domanskyi, PhD
Academy Research Fellow, PI
Office: +358 2941 59654
Cell: +358 50 448 4545
E-mail: andrii.domanskyi(at)helsinki.fi

Institute of Biotechnology, HiLIFE
P.O.Box. 56, 00014 University of Helsinki
Street address: Viikinkaari 5D, Biocenter 2, room 6028b

 

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Andrii Domanskyi, Ph.D.

Neuroprotective microRNAs, trophic factors and endoplasmic reticulum (ER) stress in adult dopaminergic neurons: significance for Parkinson's disease

SHORT RESUME:
2015-present: Research Team Leader, Academy of Finland Research fellow, Institute of Biotechnology, University of Helsinki, Finland
2014-2015: Postdoctoral scientist, Prof. Mart Saarma laboratory, Institute of Biotechnology, University of Helsinki, Finland
2007-2014: Postdoctoral scientist, Prof. Günther Schütz laboratory, German Cancer Research Center (DKFZ), Heidelberg, Germany
PhD 2007 Faculty of Medicine, University of Helsinki, Finland
MSc 2000 Faculty of Molecular and Biological Physics, Moscow Institute of Physics and Technology, Russia

MEMBERS OF THE TEAM
Piotr Chmielarz (postdoctoral fellow)
Julia Konovalova, Suvi Pöyhönen (PhD students)
Safak Er, Ilmari Parkkinen, Shirin Soleimanbeigi (MSc students)

Paula Collin-Olkkonen (technical assistant)

COLLABORATORS
Prof. Mart Saarma, Prof. Raimo Tuominen, Dr. Mikko Airavaara, Dr. Anne Panhelainen (University of Helsinki)
Dr. Kelvin Luk (University of Pennsylvania, USA)
Dr. Ilya Vinnikov (Shanghai Jiao Tong University, China)
Dr. Petri Auvinen (DNA Sequencing and Genomics lab, Institute of Biotechnology, University of Helsinki)
Dr. Petteri Piepponen (Division of Pharmacology and Pharmacotherapy,University of Helsinki)
Prof. Timo Otonkoski (Biomedicum Stem Cell Centre, University of Helsinki)
Prof. Konstantin Khodosevich (Biotech Research and Innovation Center, University of Copenhagen, Denmark)
Dr. Witold Konopka (Nencki Institute of Experimental Biology, Poland)

RESEARCH INTERESTS
Our research is focused on using transgenic rodent models to study mechanisms of dopaminergic (DA) neurons’ degeneration in Parkinson’s disease. We utilize tissue-specific inducible CreERT2/LoxP system, virus-mediated transgenesis, and CRISPR-Cas9 to introduce specific genetic modifications to rodent dopaminergic neurons in vivo, and study the progression of mutant phenotype at defined time points. These approaches allow us to study the interplay between neurotrophic factors (such as CDNF and MANF), microRNAs (miRs) and their target genes in protecting dopaminergic neurons against various forms of cellular stress. Our aim is to find putative neuroprotective microRNAs, identify their target genes and pathways, and evaluate their activity in promoting survival of dopaminergic neurons in vitro and in vivo. In close collaboration with Dr. Airavaara and Prof. Tuominen we also investigate pathways regulating proliferation, migration and differentiation of neural stem cells and astrocytes, and evaluate the possibilities to use these cells for restoration of the dopamine system.


CURRENT PROJECTS

ANDRII PROJECTS

  • Recent findings suggest that microRNAs can facilitate neuroprotective and neurorestorative effects of CDNF and MANF on dopaminergic neurons (Fig. 1). The expression of such microRNAs would be induced after CDNF or MANF treatment, whereas in dopaminergic neurons derived from PD patients’ iPSCs and in dopaminergic neurons from 6-OHDA-lesioned mice the levels of neuroprotective microRNAs would be reduced. We aim to identify and characterize such neuroprotective microRNAs and evaluate their activity in promoting survival of dopaminergic neurons in vitro and in vivo.
  • Induced and controlled migration and differentiation of endogenous neural stem cells in the adult organism offers an attractive opportunity for restoring neuronal populations and networks in neurodegenerative conditions, such as stroke and Parkinson’s disease. We study molecular pathways regulating survival, proliferation, migration, and differentiation of neural stem cells in vitro and in vivo. We have developed medium throughput and high content screening assays to search for genes and molecules affecting proliferation and differentiation of cultured primary neural stem cells. We also study the mechanisms to induce transdifferentiation of astrocytes towards neurons in stroke models.
  • We create and produce lentiviral vectors for transduction of different cellular populations and utilize lentivirus- and adeno-associated virus (AAV)-based CRISPR-Cas9 systems to introduce mutations to selected genes (including microRNAs) in cultured cells and in vivo.
  • Selective and inducible deletion of Dicer in adult dopaminergic neurons results in the loss of Dicer-dependent microRNAs that affects neuronal physiology and eventually leads to progressive degeneration of this neuronal population. We study the early effects of microRNAs depletion on the physiological properties of the dopamine system, such as dopamine release and re-uptake at neuronal terminals, and on the behavioural phenotype of mutant animals.

PAST FINDINGS
We have shown that the microRNA-processing enzyme Dicer is reduced in the ventral midbrain of Parkinson’s disease patients and aged mice, and microRNAs expression profiles in dopaminergic neurons alter with age. Moreover, a tissue-specific conditional ablation of Dicer in adult mouse DA neurons leads to their progressive loss followed by a decline of striatal dopamine content and severe behavioural deficits. This work utilised tissue-specific tamoxifen (Tam)-inducible CreERT2/LoxP system in mice that offer a precise temporal control over CreERT2 activity allowing studying the progression of mutant phenotype at defined time points after genetic deletion. We have studied pro-survival pathways in adult DA neurons demonstrating that several genes such as Tif-Ia, Pten, Foxa1 and Foxa2, and Dicer1 are crucial for the maintenance of this neuronal population.

FUNDING
Academy of Finland
Tekes 3i Regeneration
HiLIFE

SELECTED PUBLICATIONS

  1. Tseng KY, Anttila JE, Khodosevich K, Tuominen RK, Lindahl M, Domanskyi A, Airavaara M (2017) MANF promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke. Mol Therapy
  2. Tseng KY, Danilova T, Domanskyi A, Saarma M, Lindahl M, Airavaara M (2017) MANF is essential for neurite extension and neuronal migration in the developing cortex. eNeuro
  3. Chmielarz P, Konovalova J, Najam SS, Alter H, Piepponen TP, Erfle H,Sonntag K, Schütz G, Vinnikov IA, Domanskyi A, (2017) Dicer and microRNAs protect adult dopamine neurons. Cell Death Dis, 28:e2813
  4. Domanskyi A, Saarma M, Airavaara M (2015) Prospects of neurotrophic factors for Parkinson's disease: comparison of protein and gene therapy. Hum Gene Ther, 26: 550-559
  5. Domanskyi A, Alter H, Vogt MA, Gass P, Vinnikov IA (2014)Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance. Front Cell Neurosci, 8 (doi 10.3389/fncel.2014.00275)
  6. Domanskyi A, Geißler C, Vinnikov IA, Alter H, Schober A, Vogt MA, Gass P, Parlato R, Schütz, G (2011) Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. FASEB J 25, 2898-2910
  7. Rieker C, Engblom D, Kreiner G, Domanskyi A, Schober A, Stotz S, Neumann M, Yuan X, Grummt I, Schütz G, Parlato R (2011) Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling. J Neurosci 31, 453-460