TY - JOUR AU - Penke, Botond AU - Szűcs, Mária AU - Bogár, Ferenc TI - Alzheimer-kór: le tudjuk-e lassítani a betegséget, lesz-e oki terápia? JF - BIOKÉMIA: A MAGYAR BIOKÉMIAI EGYESÜLET FOLYÓIRATA J2 - BIOKÉMIA VL - 47 PY - 2023 IS - 2 SP - 10 EP - 29 PG - 20 SN - 0133-8455 UR - https://m2.mtmt.hu/api/publication/34030642 ID - 34030642 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Szűcs, Mária AU - Tóth, Gábor TI - A 80 éves Penke Botond köszöntése JF - MAGYAR KÉMIKUSOK LAPJA J2 - MAGY KEM LAP VL - 78 PY - 2023 IS - 3 SP - 95 SN - 0025-0163 UR - https://m2.mtmt.hu/api/publication/33773509 ID - 33773509 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Szűcs, Mária AU - Bogár, Ferenc TI - New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 6 PG - 23 SN - 1661-6596 DO - 10.3390/ijms24065383 UR - https://m2.mtmt.hu/api/publication/33702944 ID - 33702944 N1 - ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, GINOP-2.3.2-15-2016-00034, GINOP-2.3.2-15-2016-00060 Funding text 1: This research was funded by National Research Development and Innovation Office (NKFIH), grant numbers GINOP-2.3.2-15-2016-00060 and GINOP-2.3.2-15-2016-00034. AB - Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60–80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research. LA - English DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Szűcs, Mária AU - Bogár, Ferenc TI - Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis JF - MOLECULES J2 - MOLECULES VL - 25 PY - 2020 IS - 7 PG - 29 SN - 1420-3049 DO - 10.3390/molecules25071659 UR - https://m2.mtmt.hu/api/publication/31277461 ID - 31277461 LA - English DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Fülöp, Lívia AU - Szűcs, Mária AU - Frecska, Ede TI - The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases JF - CURRENT NEUROPHARMACOLOGY J2 - CURR NEUROPHARMACOL VL - 16 PY - 2018 IS - 1 SP - 97 EP - 116 PG - 20 SN - 1570-159X DO - 10.2174/1570159X15666170529104323 UR - https://m2.mtmt.hu/api/publication/3315334 ID - 3315334 N1 - Funding Agency and Grant Number: [KTIA_13_NAP-A-III/7]; [KTIA_13_NAP-A-II/7]; [GINOP-2.3.2-15-201600060] Funding text: This work was supported by the grants KTIA_13_NAP-A-III/7, KTIA_13_NAP-A-II/7 and GINOP-2.3.2-15-201600060. AB - Background: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. Methods: Research articles on Sigma-1 receptor were reviewed. Results: ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. Conclusion: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity. LA - English DB - MTMT ER - TY - JOUR AU - Muranyi, M AU - Cinar, Resat AU - Kékesi, Orsolya Sára AU - Birkás, Erika AU - Fábián, Gabriella AU - Bozó, Bea AU - Zentai, A AU - Tóth, Géza AU - Kicsi, EG AU - Macsai, M AU - Dochnal, Roberta AU - Szabó, Gyula AU - Szűcs, Mária TI - Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists JF - BIOMED RESEARCH INTERNATIONAL J2 - BIOMED RES INT VL - 2013 PY - 2013 PG - 9 SN - 2314-6133 DO - 10.1155/2013/501086 UR - https://m2.mtmt.hu/api/publication/2486869 ID - 2486869 AB - Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity". LA - English DB - MTMT ER - TY - JOUR AU - Cinar, Resat AU - Kékesi, Orsolya Sára AU - Birkás, Erika AU - Fábián, Gabriella AU - Schmidhammer, H AU - Szűcs, Mária TI - Lack of Regulatory Changes of mu-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity. JF - CURRENT PHARMACEUTICAL DESIGN J2 - CURR PHARM DESIGN VL - 19 PY - 2013 SP - 7348 EP - 7354 PG - 7 SN - 1381-6128 DO - 10.2174/138161281942140105161245 UR - https://m2.mtmt.hu/api/publication/2429176 ID - 2429176 AB - Here we have studied regulatory changes of mu-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting mu-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of mu-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous mu-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of mu-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that mu-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist-directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence. LA - English DB - MTMT ER - TY - JOUR AU - Szűcs, Mária TI - Receptor-kutatók kapták a 2012. évi kémiai Nobel-díjat JF - MAGYAR KÉMIKUSOK LAPJA J2 - MAGY KEM LAP VL - 68 PY - 2013 IS - 2 SP - 39 EP - 41 PG - 3 SN - 0025-0163 UR - https://m2.mtmt.hu/api/publication/2217446 ID - 2217446 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Toth, AM AU - Földi, István AU - Szűcs, Mária AU - Janáky, Tamás TI - Intraneuronal β-amyloid and its interactions with proteins and subcellular organelles JF - ELECTROPHORESIS J2 - ELECTROPHORESIS VL - 33 PY - 2012 IS - 24 SP - 3608 EP - 3616 PG - 9 SN - 0173-0835 DO - 10.1002/elps.201200297 UR - https://m2.mtmt.hu/api/publication/2202294 ID - 2202294 AB - Amyloidogenic aggregation and misfolding of proteins are linked to neurodegeneration. The mechanism of neurodegeneration in Alzheimer's disease, which gives rise to severe neuronal death and memory loss, is not yet fully understood. The amyloid hypothesis remains the most accepted theory for the pathomechanism of the disease. It was suggested that beta-amyloid accumulation may play a key role in initiating the neurodegenerative processes. The recent intracellular beta-amyloid (iA beta) hypothesis emphasizes the primary role of iA beta to initiate the disease by interaction with cytoplasmic proteins and cell organelles, thereby triggering apoptosis. Sophisticated methods (proteomics, protein microarray, and super resolution microscopy) have been used for studying iA beta interactions with proteins and membraneous structures. The present review summarizes the studies on the origin of iA beta and the base of its neurotoxicity: interactions with cytosolic proteins and several cell organelles such as endoplasmic reticulum, endosomes, lysosomes, ribosomes, mitochondria, and the microtubular system. LA - English DB - MTMT ER - TY - JOUR AU - Keresztes, Attila AU - Birkás, Erika AU - Pahi, A AU - Tóth, Géza AU - Bakota, L AU - Gulya, Károly AU - Szűcs, Mária TI - Pharmacology of a new tritiated endomorphin-2 analog containing the proline mimetic cis-2-aminocyclohexanecarboxylic acid JF - PEPTIDES J2 - PEPTIDES VL - 32 PY - 2011 IS - 4 SP - 722 EP - 728 PG - 7 SN - 0196-9781 DO - 10.1016/j.peptides.2011.01.017 UR - https://m2.mtmt.hu/api/publication/1868184 ID - 1868184 AB - As part of ongoing work aimed at generating proteolytically stable, readily applicable, radiolabeled endomorphin-2 (EM-2) analogs for elucidation of the topological requirements of peptide binding to mu-opioid receptors, we report here on the synthesis, radiolabeling, binding kinetics and binding site distribution of an EM-2 analog in which Pro(2) is replaced by 2-aminocyclohexanecarboxylic acid, ACHC. [H-3][(1S,2R)ACHC](EM)-E-2-2 (specific activity 63.49 Ci x mmol(-1)) bound specifically to its binding sites with high affinity (K-D = 0.55 +/- 0.06 nM) and saturably, yielding a receptor density, B-max of 151 +/- 4 fmol x mg protein(-1) in rat brain membranes. A similar affinity value was obtained in kinetic assays. Both Na+ and Gpp(NH)p decreased the affinity, proving the agonist character of the radioligand. Specific mu-opioid ligands displaced the radioligand with much higher affinities than did delta- and kappa-ligands. The autoradiographic distribution of the binding sites of [H-3][(1S,2R)ACHC](EM)-E-2-2 agreed well with the known locations of the mu-opioid receptors in the rat brain. In consequence of its high affinity, selectivity and enzymatic resistance [19], the new radioligand will be a good tool in studies of the topographical requirements of mu-opioid-specific peptide binding. (C) 2011 Elsevier Inc. All rights reserved. LA - English DB - MTMT ER -