Our long-standing research interest is the study of cellular mechanisms that underlie neurodegeneration and neuroinflammation in CNS pathologies, with the main focus on Parkinson’s disease. We work towards the in-depth understanding of disease mechanisms, by using in vivo and in vitro systems and integrating omics approaches with advanced imaging and molecular biology tools, to evaluate and identify novel disease-modifying therapeutics, allowing basic knowledge of disease molecular events to be translated into promising therapeutics for Parkinson’s disease and other associated disorders.
Synaptic dysfunction mechanisms in Parkinson’s disease
Description
A common delineator of neurological disorders is synaptic dysfunction due to perturbations in physiological synapse structure and function that can be either the cause or the consequence in specific pathologies. Synaptic dysfunction has been considered as an end-point incident in neurodegenerative diseases. This has recently been challenged due to advancements in disease modeling that have revealed unexpected early-occurring dysregulations at the synapse level in late-onset CNS disorders. Our team uses mouse and human-based experimental models of familial Parkinson’s disease to show how neuronal integrity and the structure/function of synapses are affected, and identify the underlying molecular mechanisms. By integrating transcriptomics and proteomics analyses of experimental systems at both neuronal and synapse level, we identify key mediators of synaptic dysfunction and validate their mode of action using gene targeting and advanced imaging in in vitro (2D & microfluidic devices) and in vivo settings. Our ultimate goal is to identify novel disease modifying therapeutics that can inhibit aggregation processes and/ or restore synaptic balance in Parkinson’s disease.
Members
Elissavet Akrioti, Aristofanis Stavrou, Konstantina Charmpi, Katerina Segklia, Georgia Kouroupi, Rebecca Matsas
Collaborators
Paraskevi Koutsoudaki & Sofia Chavaki (University of Athens)
Martina Samiotaki & Giorgos Panagiotou (Fleming Institute, Athens)
Eliezer Masliah (NIH, U.S) & Stuart Lipton (UCSD, U.S)
NeuroPore (U.S) & Panorama Research (U.S)
RNA metabolism dysregulation in αSynuclein-mediated neurodegeneration
Description
The inter-relation between αSynuclein pathological aggregation and neurodegeneration in Parkinson’s disease is widely accepted, however the initiating molecular events that bring them together remain unknown. By combining both mouse and human-based models of αSynucleinopathy we analyze the specific subcellular interactomes of aSyn by advanced fractionation, large scale targeted proteomics and single molecule imaging tracking. Our focus is to delineate how pathological αSynuclein disrupts assembly of various RNA-binding proteins into ribonucleotide-protein complexes to disrupt ribostasis and mRNA local translation at the synapse.
Members
Panagiotis Chandris, Konstantina Charmpi, Nassia Antoniou, Georgia Kouroupi, Rebecca Matsas
Martina Samiotaki & Giorgos Panagiotou (Fleming Institute, Athens)
Scott Ryan (University of Guelph, Canada) & Brian English (Janelia, U.S)
Relevant publications
Antoniou G, Prodromidou K, Kouroupi G, Boumpoureka I, Samiotaki M, Panayotou M, Xilouri M, Kloukina I, Stefanis L, Grailhe R, Taoufik E and Matsas R. High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson's Disease. npj Parkinson’s Disease, 2021
Parkinson’s disease as a neurodevelopmental disorder
Description
Despite intensive research, we are currently faced with a complete lack of therapeutics for PD, underlying the importance of “digging in” neurodegeneration mechanisms using unbiased thinking.
Our team recently demonstrated early signs of molecular defects in iPSC-derived neural stem cells from patients with familial Parkinson’s disease (Akrioti et al, Biomolecules, 2022), a model that exhibits disrupted synaptic connectivity at early stages of neuronal differentiation, which deteriorate upon neuronal maturation. Beyond the accepted notion that pathological αSynuclein leads to pathology of neurons in a cell-autonomous way in adulthood, we investigate the non-cell autonomous driven neurodegenerative mechanisms arising from complex interactions between CNS resident cells such as microglia and neurons throughout early development to adulthood in both mouse and human-based (2D &3D) systems.
Members
Panagiotis Chandris, Elissavet Akrioti, Olympia Apokotou, Katerina Segklia, Georgia Kouroupi, Rebecca Matsas
Collaborators
Timokratis Karamitros (Hellenic Pasteur Institute, Athens)
Aleksandra Deczkowska & Valentina Libri (Institut Pasteur-Paris)
Relevant publications
Early signs of molecular defects in iPSC-derived neural stems cells from patients with familial Parkinson’s disease. Elissavet Akrioti, Timokratis Karamitros, Panagiotis Garavelas, Georgia Kouroupi, Rebecca Matsas, Era Taoufik (accepted in Biomolecules, 2022)
Development of a multiparametric morphofunctional platform to uncover disease mechanisms and druggable targets in patient derived cells: study of neuron-glia dynamics in alpha synuclein-mediated pathologies. 1019-DiseasePHENOTarget, HFRI, PI: R. Matsas - (E. Taoufik Participation as WP Leader). Duration: May 2021-April 2024
Systematic development and commercial exploitation of novel compounds inhibiting alpha-synuclein aggregation. Τ2ΕΔΚ-02813 AlphaSyn MIS 5131418, EPAnEK – NSRF 2014-2020, PI: R. Matsas - (E. Taoufik Participation as Team Member). Duration: September 2021-December 2023
Creation of a Virtual Research Unit for Studies in Neurodegenerative Diseases. PIs Rebecca Matsas (HPI) and Chiara Zurzolo (IP-Paris) Grant number: PIU2020-2025. PI: R. Matsas – (E. Taoufik Participation as Team Member). Duration: 5 years, October 2020- September 2025
Flagship Action for Neurodegenerative Diseases on the basis of Personalized Medicine, MIS 2018SΕ01300001, GSRI –NSFR 2014-2020 HPI coordinator: R. Matsas – (E. Taoufik as Participation as Team member). Duration: May 2020 - May 2022
High Technology Infrastructure for Preclinical Studies and Provision of Specialized Services for Infectious and Neurodegenerative Diseases (Institutional project), MIS 5066768, Funding source: Priority Axis «Strengthening the Mechanisms and Investments of SMEs of the Attica Region in Research and Innovation» funded by the Operational Program «Attiki 2014-2020» (NSFR 2014-2020). Coordinator: E. Karagouni – (E. Taoufik Participation as Team member). Duration: July 2021-December 2023
Infrastructure for preclinical and early-phase clinical development of drugs, therapeutics and biomedical devices, EPAnEK – NSRF 2014-2020 under the action «Support and development of national research infrastructure». Grant number: EATRIS-GR MIS 5028091 Coordinator: E. Karagouni – (E. Taoufik Participation as Team member). Duration: January 2019 – December 2022
Mechanisms of synaptic dysfunction in human induced pluripotent stem cell-based 2D- and 3D-models of familial Parkinson’s disease, 899-PARKINSynapse, HFRI. PI: Georgia Kouroupi- (E. Taoufik Participation as WP Leader). Duration: November 2018-December 2021
Akrioti Ε, Karamitros Τ, Gkaravelas P, Kouroupi G, Matsas R, Taoufik E. Early signs of molecular defects in iPSC-derived neural stems cells from patients with familial Parkinson’s disease. Accepted for publication in Biomolecules, June 2022
Antoniou G, Prodromidou K, Kouroupi G, Boumpoureka I, Samiotaki M, Panayotou M, Xilouri M, Kloukina I, Stefanis L, Grailhe R, Taoufik E and Matsas R. (2022) High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson's Disease. NPJ Parkinsons Dis. Feb 11;8(1):15. doi: 10.1038/s41531-022-00278-y npj
Kouroupi G, Prodromidou K, Papastefanaki F, Taoufik E, Matsas R (2022) Organoids: the third dimension of human brain development and disease. Int J Dev Biol.;66(1-2-3):23-33. doi: 10.1387/ijdb.210158gk
Kouroupi G, Antoniou N, Prodromidou K, Taoufik E, Matsas R. (2020) Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson's Disease for Drug Identification. Int J Mol Sci. Sep 26;21(19):7113. doi: 10.3390/ijms21197113
Zygogianni O, Kouroupi G, Taoufik E, Matsas R. (2020) Engraftable Induced Pluripotent Stem Cell-Derived Neural Precursors for Brain Repair. Methods Mol Biol.;2155:23-39. doi: 10.1007/978-1-0716-0655-1_3
Zygogianni O, Antoniou N, Kalomoiri M, Kouroupi G, Taoufik E, Matsas R (2019) In vivo phenotyping of familial Parkinson’s disease with human induced pluripotent stem cells: a proof-of-concept study.” Neurochem Res. Jun;44(6):1475-1493. doi: 10.1007/s11064-019-02781-w
Taoufik E, Kouroupi G, Zygogianni O, Matsas R. (2018) Synaptic dysfunction in neurodegenerative and neurodevelopmental diseases: an overview of induced pluripotent stem-cell-based disease models. Open Biol. Sep;8(9)
Kouroupi G, Taoufik E, Vlachos IS, Tsioras K, Antoniou N, Papastefanaki F, Chroni-Tzartou D, Wrasidlo W, Bohl D, Stellas D, Politis PK, Vekrellis K, Papadimitriou D, Stefanis L, Bregestovski P, Hatzigeorgiou A G., Masliah E, Matsas R (2017) Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson’s disease. Proc Natl Acad Sci U S A.