Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A Thu Lan Nguyen, Arnaud Duchon, Antigoni Manousopoulou, Nadège Loaëc, Benoît Villiers, Guillaume Pani, Meltem Karatas, Anna E Mechling, Laura-Adela Harsan, Emmanuelle Limanton, et al. To cite this version: Thu Lan Nguyen, Arnaud Duchon, Antigoni Manousopoulou, Nadège Loaëc, Benoît Villiers, et al.. Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological in- hibitor of DYRK1A. Disease Models & Mechanisms, Cambridge Company of Biologists, 2018, 11 (9), pp.dmm035634. 10.1242/dmm.035634. hal-01862465 HAL Id: hal-01862465 https://hal-univ-rennes1.archives-ouvertes.fr/hal-01862465 Submitted on 17 Jul 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. © 2018. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2018) 11, dmm035634. doi:10.1242/dmm.035634 RESEARCH ARTICLE Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A Thu Lan Nguyen1,2,3,4,5, Arnaud Duchon1,2,3,4, Antigoni Manousopoulou6, Nadegè Loaëc5, Benoît Villiers5, Guillaume Pani1,2,3,4, Meltem Karatas7,8, Anna E. Mechling8, Laura-Adela Harsan7,8, Emmanuelle Limanton9, Jean-Pierre Bazureau9, François Carreaux9, Spiros D. Garbis6,*,‡, Laurent Meijer5,‡ and Yann Herault1,2,3,4,‡ ABSTRACT INTRODUCTION Growing evidence supports the implication of DYRK1A in the Down syndrome (DS) results from the trisomy of human development of cognitive deficits seen in Down syndrome (DS) and chromosome 21 (HSA21). It is still the most frequent intellectual Alzheimer’s disease (AD). We here demonstrate that pharmacological disability, affecting 1 newborn per 700 births. Among the most inhibition of brain DYRK1A is able to correct recognition memory common DS features are hypotonia, dysmorphic features and deficits in three DS mouse models with increasing genetic complexity intellectual disability (Sureshbabu et al., 2011; Morris et al., 1982). Although children with DS show good socialization skills – [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a. – Overexpressed DYRK1A accumulates in the cytoplasm and at the encompassing social relations, friendship and leisure activities synapse. Treatment of the three DS models with the pharmacological they exhibit difficulties in communication abilities, i.e. the daily use DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A of receptive, expressive and written language (Marchal et al., 2016). activity and corrects the novel object cognitive impairment observed in They experience troubles in daily life skills, such as self-caring, these models. Brain functional magnetic resonance imaging reveals eating, toileting, dressing, behaving safely, and conceptualizing that this cognitive improvement is paralleled by functional connectivity time and money. Improving the intellectual quotient of DS people remodelling of core brain areas involved in learning/memory would allow them to achieve more independence, increase their processes. The impact of Dyrk1a trisomy and L41 treatment vigilance and globally improve their quality of life. on brain phosphoproteins was investigated by a quantitative Among candidate genes explaining intellectual disabilities in DS people, the dual specificity tyrosine-phosphorylation-regulated phosphoproteomics method, revealing the implication of synaptic DYRK1A (synapsin 1) and cytoskeletal components involved in synaptic kinase 1A, , is located in the DS chromosome 21 critical response and axonal organization. These results encourage the region (Walte et al., 2013; Duchon and Herault, 2016). It encodes development of DYRK1A inhibitors as drug candidates to treat a serine/threonine kinase which has numerous substrates. Two cognitive deficits associated with DS and AD. nuclear localization signals confer nuclear activity to this kinase (Alvarez et al., 2007), through interactions with transcription factors KEY WORDS: DYRK1A, Kinase inhibitor, Leucettine, Down including GLI1 (Mao et al., 2002), RNA POL II (Di Vona et al., syndrome, Synapsin 2015) or splicing factors like cyclin L2 (Graaf et al., 2004). In the cytoplasm, DYRK1A phosphorylates cytoskeletal substrates such as β-tubulin, MAP1A or MAP1B (Ori-McKenney et al., 2016; Murakami et al., 2012; Scales et al., 2009). DYRK1A plays a role in 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of cell cycle regulation by phosphorylating the cyclin-dependent Translational Medicine and Neurogenetics, 67400 Illkirch, France. 2Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France. 3Institut National de kinase (CDK) inhibitor KIP1 (also known as CDKN1B) in cultured la Santéet de la Recherche Médicale, U964, 67400 Illkirch, France. 4Universitéde hippocampal neurons and in embryonic mouse brain (Soppa et al., Strasbourg, 67400 Illkirch, France. 5ManRos Therapeutics, Perharidy Research in vitro Center, 29680 Roscoff, Bretagne, France. 6Faculty of Medicine/Cancer Sciences & 2014) and LIN52 (Litovchick et al., 2011). Through its Clinical and Experimental Medicine, University of Southampton, Center for ‘priming’ activity for glycogen synthase kinase 3β (GSK-3β)- Proteomic Research, Life Sciences Building 85, Highfield, Southampton SO17 1BJ, dependent phosphorylation, DYRK1A regulates the nuclear/ UK. 7Laboratory of Engineering, Informatics and Imaging (ICube), Integrative multimodal imaging in healthcare (IMIS), UMR 7357, and University Hospital cytoplasmic localization of the NFAT transcription factors Strasbourg, Department of Biophysics and Nuclear Medicine, University of (Arron et al., 2006). At the synaptic level, DYRK1A binds to 8 Strasbourg, 67400 Illkirch, France. Department of Radiology, Medical Physics, N-methyl-D-aspartate receptor subunit 2A (GLUN2A; also known Medical Center – University of Freiburg, Breisacher Strasse 60a, 79106 Freiburg, Germany. 9Universitéde Rennes 1, ISCR (Institut des sciences chimiques de as GRIN2A) and synaptojanin 1 (SYNJ1) (Chen et al., 2014; Grau Rennes)-UMR, 6226, 35000 Rennes, France. et al., 2014) and phosphorylates amphyphysin 1 (Murakami et al., *Present address: Proteome Exploration Laboratory, Division of Biology and Biological Engineering, Beckman Institute, California Institute of Technology, 2012) and GLUN2A (Grau et al., 2014). These are examples of Pasadena, CA 91125, USA. different biological brain functions controlled by DYRK1A which are probably dysregulated when DYRK1A is overexpressed in DS, ‡Authors for correspondence ([email protected]; [email protected]; [email protected]) leading to cognitive impairments. Several mouse models overexpressing DYRK1A have been S.D.G., 0000-0002-1050-0805; L.M., 0000-0003-3511-4916; Y.H., 0000-0001- described. The first one, Tg(CEPHY152F7)12Hgc, carries a single 7049-6900 copy of a yeast artificial chromosome (YAC) containing a 570 kb This is an Open Access article distributed under the terms of the Creative Commons Attribution fragment of human DNA encompassing TTC3, DYRK1A and License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, KCNJ6 distribution and reproduction in any medium provided that the original work is properly attributed. This model shows no strong defect in spatial learning and memory, but displays less crossing of the site where the platform Received 11 May 2018; Accepted 1 August 2018 was during the probe test in the Morris water maze (MWM) task Disease Models & Mechanisms 1 RESEARCH ARTICLE Disease Models & Mechanisms (2018) 11, dmm035634. doi:10.1242/dmm.035634 (Smith et al., 1997). Another model, Tg(MT1A-Dyrk1a)#Xest (Freund et al., 2003; Wilson and Nicoll, 2002), compromising its (#=9 or 33), was produced by expressing the Dyrk1a rat therapeutic use. Furthermore, DYRK1A is less sensitive to EGCG complementary DNA (cDNA) under the control of the [half-maximal inhibitory concentration (IC50), 0.33 µM] than metallothionein 1a exogenous promoter (Altafaj et al., 2001). vimentin (IC50, 0.003 µM) and the laminin receptor (IC50, These mice demonstrated impairments in neuromotor development 0.04 µM) (Khan et al., 2006; Yang et al., 2009). Cognitive and hyperactivity evaluated in treadmill performance and rotarod restoration in trisomic mice by EGCG might thus be due to tests (Martínez de Lagrán et al., 2004). They also display defects in inhibition of targets other than DYRK1A. Consequently, visuospatial learning and memory in the MWM task (Martínez de alternative pharmacological inhibitors have started to emerge Lagrán et al., 2004; Pons-Espinal et al., 2013), as well as in (Kim et al., 2016; Nakano-Kobayashi et al., 2017; Nguyen et al., recognition memory revealed in the novel object recognition (NOR) 2017). Nevertheless, all available results clearly demonstrate task (de la Torre et al., 2014). A third model, Tg(DYRK1A)36Wjs, the implication of DYRK1A in DS intellectual deficiencies and was generated using a bacterial artificial chromosome (BAC) the beneficial