TY - JOUR AU - Oláh, Judit AU - Norris, Vic AU - Lehotzky, Attila AU - Ovádi, Judit TI - Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP JF - CELLS J2 - CELLS-BASEL VL - 13 PY - 2024 IS - 4 SN - 2073-4409 DO - 10.3390/cells13040338 UR - https://m2.mtmt.hu/api/publication/34597136 ID - 34597136 N1 - Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, H-1117, Hungary Laboratory of Bacterial Communication and Anti-Infection Strategies, EA 4312, University of Rouen, Mont Saint Aignan, 76821, France Export Date: 13 March 2024; Cited By: 0; Correspondence Address: J. Oláh; Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, H-1117, Hungary; email: olah.judit@ttk.hu AB - Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes. LA - English DB - MTMT ER - TY - JOUR AU - Norris, Vic AU - Oláh, Judit AU - Krylov, Sergey N. AU - Uversky, Vladimir N. AU - Ovádi, Judit TI - The Sherpa hypothesis: Phenotype-Preserving Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes JF - NPJ SYSTEMS BIOLOGY AND APPLICATIONS J2 - NPJ SYST BIOL APPL VL - 9 PY - 2023 IS - 1 SN - 2056-7189 DO - 10.1038/s41540-023-00291-8 UR - https://m2.mtmt.hu/api/publication/34061155 ID - 34061155 N1 - Laboratory of Microbiology Signals and Microenvironment, University of Rouen, Mont Saint Aignan, 76821, France Institute of Enzymology, Research Centre for Natural Sciences, Budapest, H-1117, Hungary Centre for Research on Biomolecular Interactions, York University, Toronto, ON M3J1P3, Canada Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, 33612, FL, United States Export Date: 01 August 2023; Cited By: 0; Correspondence Address: V. Norris; Laboratory of Microbiology Signals and Microenvironment, University of Rouen, Mont Saint Aignan, 76821, France; email: victor.norris@univ-rouen.fr AB - Intrinsically disordered proteins (IDPs), which can interact with many partner proteins, are central to many physiological functions and to various pathologies that include neurodegeneration. Here, we introduce the Sherpa hypothesis, according to which a subset of stable IDPs that we term Phenotype-Preserving Disordered Proteins (PPDP) play a central role in protecting cell phenotypes from perturbations. To illustrate and test this hypothesis, we computer-simulate some salient features of how cells evolve and differentiate in the presence of either a single PPDP or two incompatible PPDPs. We relate this virtual experiment to the pathological interactions between two PPDPs, α-synuclein and Tubulin Polymerization Promoting Protein/p25, in neurodegenerative disorders. Finally, we discuss the implications of the Sherpa hypothesis for aptamer-based therapies of such disorders. LA - English DB - MTMT ER - TY - JOUR AU - Oláh, Judit AU - Lehotzky, Attila AU - Szénási, Tibor AU - Berki, Tímea AU - Ovádi, Judit TI - Modulatory Role of TPPP3 in Microtubule Organization and Its Impact on Alpha-Synuclein Pathology. JF - CELLS J2 - CELLS-BASEL VL - 11 PY - 2022 IS - 19 PG - 21 SN - 2073-4409 DO - 10.3390/cells11193025 UR - https://m2.mtmt.hu/api/publication/33163273 ID - 33163273 AB - Parkinson's disease is characterized by locomotion deficits, dopaminergic neuronal loss and alpha-synuclein (SYN) aggregates; the Tubulin Polymerization Promoting Protein (TPPP/p25 or TPPP1) is also implicated in these processes. The moonlighting and chameleon TPPP1 modulates the dynamics/stability of the multifunctional microtubule network by promoting its acetylation and bundling. Previously, we identified the microtubule-associated TPPP3, a homologue of TPPP1 lacking its N-terminus; however, its involvement in physiological or pathological processes was not elucidated. In this work, we have shown the modulatory role of TPPP3, similarly to TPPP1, in microtubule organization, as well as its homo- and hetero-associations with TPPP1. TPPP3, in contrast to TPPP1, virtually does not bind to SYN; consequently, it does not promote SYN aggregation. Its anti-aggregative potency is achieved by counteracting the formation of the TPPP1-SYN pathological complex/aggregation leading to Parkinsonism. The interactions of TPPP3 have been determined and quantified in vitro with recombinant human proteins, cell extracts and in living human cells using different methods including bifunctional fluorescence complementation. The tight association of TPPP3 with TPPP1, but not with SYN, may ensure a unique mechanism for its inhibitory effect. TPPP3 or its selected fragments may become a leading agent for developing anti-Parkinson agents. LA - English DB - MTMT ER - TY - JOUR AU - Oláh, Judit AU - Szénási, Tibor AU - Lehotzky, Attila AU - Norris, Victor AU - Ovádi, Judit TI - Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 3 SN - 1661-6596 DO - 10.3390/ijms23031550 UR - https://m2.mtmt.hu/api/publication/32661321 ID - 32661321 N1 - Institute of Enzymology, Research Centre for Natural Sciences, ELKH, Budapest, 1117, Hungary Laboratory of Microbiology Signals and Microenvironment, University of Rouen, Mont Saint Aignan, 76821, France Export Date: 17 February 2022 Correspondence Address: Ovádi, J.; Institute of Enzymology, Hungary; email: ovadi.judit@ttk.hu Funding details: Hungarian Scientific Research Fund, OTKA, PD-124061 Funding details: Magyar Tudományos Akadémia, MTA, BO/340/19 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding text 1: Funding: This work was funded by the Hungarian National Research, Development and Innovation Office Grants OTKA [PD-124061] to T. Szénási, and János Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/340/19] to J. Oláh, respectively. LA - English DB - MTMT ER - TY - CHAP AU - Oláh, Judit AU - Lehotzky, Attila AU - Szénási, Tibor AU - Ovádi, Judit ED - Lin, Zhang TI - A potential innovative therapy for Parkinson’s disease: Selective destruction of the pathological assemblies of alpha-synuclein T2 - Dementia in Parkinson's Disease PB - IntechOpen CY - London SN - 9781839688447 PY - 2022 DO - 10.5772/intechopen.97271 UR - https://m2.mtmt.hu/api/publication/31897147 ID - 31897147 LA - English DB - MTMT ER - TY - JOUR AU - Oláh, Judit AU - Lehotzky, Attila AU - Szénási, Tibor AU - Ovádi, Judit TI - Anti-aggregative effect of the antioxidant dj-1 on the tppp/p25-derived pathological associations of alpha-synuclein JF - CELLS J2 - CELLS-BASEL VL - 10 PY - 2021 IS - 11 SN - 2073-4409 DO - 10.3390/cells10112909 UR - https://m2.mtmt.hu/api/publication/32477494 ID - 32477494 N1 - Export Date: 4 November 2021 Correspondence Address: Oláh, J.; Cell Architecture Lab, Hungary; email: olah.judit@ttk.hu Correspondence Address: Ovádi, J.; Cell Architecture Lab, Hungary; email: ovadi.judit@ttk.hu Funding details: Hungarian Scientific Research Fund, OTKA, PD-124061 Funding details: Magyar Tudományos Akadémia, MTA, BO/340/19 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding text 1: Funding: This work was funded by the Hungarian National Research, Development and Innovation Office Grants OTKA [PD-124061] to T. Szénási, and by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/340/19] to J.O. (Judit Oláh). AB - DJ-1, a multi-functional protein with antioxidant properties, protects dopaminergic neurons against Parkinson’s disease (PD). The oligomerization/assembly of alpha-synuclein (SYN), promoted by Tubulin Polymerization Promoting Protein (TPPP/p25), is fatal in the early stage of PD. The pathological assembly of SYN with TPPP/p25 inhibits their proteolytic degradation. In this work, we identified DJ-1 as a new interactive partner of TPPP/p25, and revealed its influence on the association of TPPP/p25 with SYN. DJ-1 did not affect the TPPP/p25-derived tubulin polymerization; however, it did impede the toxic assembly of TPPP/p25 with SYN. The interaction of DJ-1 with TPPP/p25 was visualized in living human cells by fluorescence confocal microscopy coupled with Bifunctional Fluorescence Complementation (BiFC). While the transfected DJ-1 displayed homogeneous intracellular distribution, the TPPP/p25-DJ-1 complex was aligned along the microtubule network. The anti-aggregative effect of DJ-1 on the pathological TPPP/p25-SYN assemblies was established by the decrease in the intensity of their intracellular fluorescence (BiFC signal) and the increase in the proteolytic degradation of SYN complexed with TPPP/p25 due to the DJ-1-derived disassembly of SYN with TPPP/p25. These data obtained with HeLa and SH-SY5Y cells revealed the protective effect of DJ-1 against toxic SYN assemblies, which assigns a new function to the antioxidant sensor DJ-1. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. LA - English DB - MTMT ER - TY - JOUR AU - Norris, Victor AU - Ovádi, Judit TI - Role of Multifunctional Cytoskeletal Filaments in Coronaviridae Infections: Therapeutic Opportunities for COVID-19 in a Nutshell JF - CELLS J2 - CELLS-BASEL VL - 10 PY - 2021 IS - 7 SN - 2073-4409 DO - 10.3390/cells10071818 UR - https://m2.mtmt.hu/api/publication/32132687 ID - 32132687 LA - English DB - MTMT ER - TY - JOUR AU - Lehotzky, Attila AU - Oláh, Judit AU - Fekete, János Tibor AU - Szénási, Tibor AU - Szabó, Edit Zsuzsanna AU - Győrffy, Balázs AU - Várady, György AU - Ovádi, Judit TI - Co-Transmission of Alpha-Synuclein and TPPP/p25 Inhibits Their Proteolytic Degradation in Human Cell Models JF - FRONTIERS IN MOLECULAR BIOSCIENCES J2 - FRONT MOL BIOSCI VL - 8 PY - 2021 PG - 15 SN - 2296-889X DO - 10.3389/fmolb.2021.666026 UR - https://m2.mtmt.hu/api/publication/32061631 ID - 32061631 LA - English DB - MTMT ER - TY - JOUR AU - Schiedel, Matthias AU - Lehotzky, Attila AU - Szunyogh, Sandor AU - Oláh, Judit AU - Hammelmann, Sören AU - Wössner, Nathalie AU - Robaa, Dina AU - Einsle, Oliver AU - Sippl, Wolfgang AU - Ovádi, Judit AU - Jung, Manfred TI - HaloTag-targeted Sirtuin rearranging ligand (SirReal) for the development of proteolysis targeting chimeras (PROTACs) against the lysine deacetylase Sirtuin 2 (Sirt2). JF - CHEMBIOCHEM J2 - CHEMBIOCHEM VL - 21 PY - 2020 IS - 23 SP - 3371 EP - 3376 PG - 6 SN - 1439-4227 DO - 10.1002/cbic.202000351 UR - https://m2.mtmt.hu/api/publication/31400077 ID - 31400077 N1 - Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Freiburg im Breisgau, 79104, Germany Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok körútja 2, Budapest, 1117, Hungary Institute of Pharmacy, Martin-Luther-University Halle–Wittenberg, Kurt-Mothes-Straße 3, Halle/Saale, 06120, Germany Institute of Biochemistry and BIOSS Centre for Biological Signalling Studies, University of Freiburg, Albertstraße 21, Freiburg im Breisgau, 79104, Germany Export Date: 2 November 2020 CODEN: CBCHF Correspondence Address: Jung, M.; Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, Germany; email: manfred.jung@pharmazie.uni-freiburg.de AB - We have discovered the sirtuin rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+-dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so-called proteolysis targeting chimera (PROTAC), enabled small molecule-induced degradation of Sirt2. Here, we report the structure-based development of a chloroalkylated SirReal that induces the degradation of Sirt2 mediated by Halo-tagged E3 ubiquitin ligases. Using this orthogonal approach for Sirt2 degradation, we show that also other E3 ligases than cereblon, such as the E3 ubiquitin ligase parkin, can be harnessed for small molecule-induced Sirt2 degradation, thereby emphasizing the great potential of parkin to be utilized as an E3 ligase for new PROTACs approaches. Thus, our study provides new insights into targeted protein degradation in general and Sirt2 degradation in particular. LA - English DB - MTMT ER - TY - JOUR AU - Oláh, Judit AU - Lehotzky, Attila AU - Szunyogh, Sándor AU - Szénási, Tibor AU - Orosz, Ferenc AU - Ovádi, Judit TI - Microtubule-Associated Proteins with Regulatory Functions by Day and Pathological Potency at Night. JF - CELLS J2 - CELLS-BASEL VL - 9 PY - 2020 IS - 2 SN - 2073-4409 DO - 10.3390/cells9020357 UR - https://m2.mtmt.hu/api/publication/31177407 ID - 31177407 N1 - Journal Article; Review AB - The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeleton, including the microtubule network. Microtubules play crucial roles achieved by their decoration with proteins/enzymes as well as by posttranslational modifications. This review focuses on the Tubulin Polymerization Promoting Protein (TPPP/p25), a new microtubule associated protein, on its "regulatory functions by day and pathological functions at night". Physiologically, the moonlighting TPPP/p25 modulates the dynamics and stability of the microtubule network by bundling microtubules and enhancing the tubulin acetylation due to the inhibition of tubulin deacetylases. The optimal endogenous TPPP/p25 level is crucial for its physiological functions, to the differentiation of oligodendrocytes, which are the major constituents of the myelin sheath. Pathologically, TPPP/p25 forms toxic oligomers/aggregates with α-synuclein in neurons and oligodendrocytes in Parkinson's disease and Multiple System Atrophy, respectively; and their complex is a potential therapeutic drug target. TPPP/p25-derived microtubule hyperacetylation counteracts uncontrolled cell division. All these issues reveal the anti-mitotic and α-synuclein aggregation-promoting potency of TPPP/p25, consistent with the finding that Parkinson's disease patients have reduced risk for certain cancers. LA - English DB - MTMT ER -