umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Ådén, Jörgen
Alternative names
Publications (10 of 27) Show all publications
Dingeldein, A. P. G., Lindberg, M. J., Ådén, J., Zhong, X., Stoll, R. & Gröbner, G. (2019). Bax to the future – A novel, high-yielding approach for purification and expression of full-length Bax protein for structural studies. Protein Expression and Purification, 158, 20-26
Open this publication in new window or tab >>Bax to the future – A novel, high-yielding approach for purification and expression of full-length Bax protein for structural studies
Show others...
2019 (English)In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 158, p. 20-26Article in journal (Refereed) Published
Abstract [en]

Mitochondria-mediated apoptosis (programmed cell death) involves a sophisticated signaling and regulatory network that is regulated by the Bcl-2 protein family. Members of this family have either pro- or anti-apoptotic functions. An important pro-apoptotic member of this family is the cytosolic Bax. This protein is crucial for the onset of apoptosis by perforating the mitochondrial outer membrane (MOM). This process can be seen as point of no return, since disintegration of the MOM leads to the release of apotogenic factors such as cytochrome c into the cytosol triggering the activation of caspases and subsequent apoptotic steps. Bax is able to interact with the MOM with both its termini, making it inherently difficult to express in E. coli. In this study, we present a novel approach to express and purify full-length Bax with significantly increased yields, when compared to the commonly applied strategy. Using a double fusion approach with an N-terminal GST-tag and a C-terminal Intein-CBD-tag, we were able to render both Bax termini inactive and prevent disruptive interactions from occurring during gene expression. By deploying an Intein-CBD-tag at the C-terminus we were further able to avoid the introduction of any artificial residues, hence ensuring the native like activity of the membrane-penetrating C-terminus of Bax. Further, by engineering a His6-tag to the C-terminus of the CBD-tag we greatly improved the robustness of the purification procedure. We report yields for pure, full-length Bax protein that are increased by an order of magnitude, when compared to commonly used Bax expression protocols.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156983 (URN)10.1016/j.pep.2019.02.004 (DOI)000462805100004 ()30738180 (PubMedID)2-s2.0-85061543221 (Scopus ID)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-04-15Bibliographically approved
Dingeldein, A. P. G., Sparrman, T., Ådén, J., Wacklin, H. P., Clifton, L. A. & Gröbner, G. (2019). Mitochondrial Membrane Organization under Oxidative Stress: Insight by Solid-State NMR and Neutron Reflectometry. Paper presented at 63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD. Biophysical Journal, 116(3), 508A-508A
Open this publication in new window or tab >>Mitochondrial Membrane Organization under Oxidative Stress: Insight by Solid-State NMR and Neutron Reflectometry
Show others...
2019 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 508A-508AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-157775 (URN)10.1016/j.bpj.2018.11.2742 (DOI)000460779802556 ()
Conference
63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD
Available from: 2019-04-10 Created: 2019-04-10 Last updated: 2019-04-10Bibliographically approved
Singh, P., Adolfsson, D. E., Ådén, J., Cairns, A. G., Bartens, C., Brännström, K., . . . Almqvist, F. (2019). Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding. Journal of Organic Chemistry, 84(7), 3887-3903
Open this publication in new window or tab >>Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
Show others...
2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed) Published
Abstract [en]

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157464 (URN)10.1021/acs.joc.8b03015 (DOI)000464250800014 ()30862161 (PubMedID)
Funder
Swedish Research Council, 2014-04673Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031The Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-06-13Bibliographically approved
Singh, P., Cairns, A. G., Adolfsson, D. E., Ådén, J., Sauer, U. H. & Almqvist, F. (2019). Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones. Organic Letters
Open this publication in new window or tab >>Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones
Show others...
2019 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052Article in journal (Refereed) Epub ahead of print
Abstract [en]

We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry Inorganic Chemistry Polymer Chemistry
Identifiers
urn:nbn:se:umu:diva-162826 (URN)10.1021/acs.orglett.9b02549 (DOI)31419146 (PubMedID)
Available from: 2019-08-30 Created: 2019-08-30 Last updated: 2019-09-03
Olsen, L. K., Cairns, A. G., Ådén, J., Moriarty, N., Cabre, S., Alamilla, V. R., . . . McKernan, D. P. (2019). Viral mimetic priming enhances α-synuclein-induced degeneration: implications for Parkinson's disease. Brain, behavior, and immunity, 80, 525-535
Open this publication in new window or tab >>Viral mimetic priming enhances α-synuclein-induced degeneration: implications for Parkinson's disease
Show others...
2019 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 80, p. 525-535Article in journal (Refereed) Published
Abstract [en]

Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson’s disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson’s disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson’s disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson’s disease.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Parkinson’s disease, Viral infection, Neuroinflammation, α-Synuclein, Neurodegeneration
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-159474 (URN)10.1016/j.bbi.2019.04.036 (DOI)000478105500051 ()31029796 (PubMedID)
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-09-10Bibliographically approved
Cairns, A. G., Vazquez-Romero, A., Mahdi-Moein, M., Ådén, J., Elmore, C. S., Takano, A., . . . Schou, M. (2018). Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy [Letter to the editor]. ACS Chemical Neuroscience, 9(11), 2542-2547
Open this publication in new window or tab >>Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
Show others...
2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 11, p. 2542-2547Article in journal, Letter (Refereed) Published
Abstract [en]

Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Alpha-synuclein, carbon-11, PET
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-151139 (URN)10.1021/acschemneuro.8b00236 (DOI)000451496200005 ()29901990 (PubMedID)
Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2018-12-19Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
Show others...
2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Jain, N., Ådén, J., Nagamatsu, K., Evans, M. L., Li, X., McMichael, B., . . . Chapman, M. R. (2017). Inhibition of curli assembly and Escherichia coli biofilm formation by the human systemic amyloid precursor transthyretin. Proceedings of the National Academy of Sciences of the United States of America, 114(46), 12184-12189
Open this publication in new window or tab >>Inhibition of curli assembly and Escherichia coli biofilm formation by the human systemic amyloid precursor transthyretin
Show others...
2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 46, p. 12184-12189Article in journal (Refereed) Published
Abstract [en]

During biofilm formation, Escherichia coli and other Enterobacteriaceae produce an extracellular matrix consisting of curli amyloid fibers and cellulose. The precursor of curli fibers is the amyloidogenic protein CsgA. The human systemic amyloid precursor protein transthyretin (TTR) is known to inhibit amyloid-β (Aβ) aggregation in vitro and suppress the Alzheimer’s-like phenotypes in a transgenic mouse model of Aβ deposition. We hypothesized that TTR might have broad antiamyloid activity because the biophysical properties of amyloids are largely conserved across species and kingdoms. Here, we report that both human WT tetrameric TTR (WT-TTR) and its engineered nontetramer-forming monomer (M-TTR, F87M/L110M) inhibit CsgA amyloid formation in vitro, with M-TTR being the more efficient inhibitor. Preincubation of WT-TTR with small molecules that occupy the T4 binding site eliminated the inhibitory capacity of the tetramer; however, they did not significantly compromise the ability of M-TTR to inhibit CsgA amyloidogenesis. TTR also inhibited amyloid-dependent biofilm formation in two different bacterial species with no apparent bactericidal or bacteriostatic effects. These discoveries suggest that TTR is an effective antibiofilm agent that could potentiate antibiotic efficacy in infections associated with significant biofilm formation.

Keywords
Amyloids, CsgA, Transthyretin, Biofilms, Curli
National Category
Chemical Sciences Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-142602 (URN)10.1073/pnas.1708805114 (DOI)000415173300053 ()29087319 (PubMedID)
Available from: 2017-12-05 Created: 2017-12-05 Last updated: 2018-06-09Bibliographically approved
Mondol, T., Ådén, J. & Wittung-Stafshede, P. (2016). Copper binding triggers compaction in N-terminal tail of human copper pump ATP7B. Biochemical and Biophysical Research Communications - BBRC, 470(3), 663-669
Open this publication in new window or tab >>Copper binding triggers compaction in N-terminal tail of human copper pump ATP7B
2016 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 470, no 3, p. 663-669Article in journal (Refereed) Published
Abstract [en]

Protein conformational changes are fundamental to biological reactions. For copper ion transport, the multi-domain protein ATP7B in the Golgi network receives copper from the cytoplasmic copper chaperone Atox1 and, with energy from ATP hydrolysis, moves the metal to the lumen for loading of copper dependent enzymes. Although anticipated, conformational changes involved in ATP7B's functional cycle remain elusive. Using spectroscopic methods we here demonstrate that the four most N-terminal metal binding domains in ATP7B, upon stoichiometric copper addition, adopt a more compact arrangement which has a higher thermal stability than in the absence of copper. In contrast to previous reports, no stable complex was found in solution between the metal-binding domains and the nucleotide-binding domain of ATP7B. Metal-dependent movement of the first four metal-binding domains in ATP7B may be a trigger that initiates the overall catalytic cycle.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
Protein-protein interactions, Metalloenzymes, Copper transport, NMR, Circular dichroism, Conformational changes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-118252 (URN)10.1016/j.bbrc.2016.01.085 (DOI)000370467100030 ()26797276 (PubMedID)
Available from: 2016-03-17 Created: 2016-03-14 Last updated: 2018-06-07Bibliographically approved
Chorell, E., Andersson, E., Evans, M. L., Jain, N., Götheson, A., Åden, J., . . . Wittung-Stafshede, P. (2015). Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts. PLoS ONE, 10(10), 1-11, Article ID e0140194.
Open this publication in new window or tab >>Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts
Show others...
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, p. 1-11, article id e0140194Article in journal (Refereed) Published
Abstract [en]

Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson’s disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-110343 (URN)10.1371/journal.pone.0140194 (DOI)000363183100087 ()26465894 (PubMedID)
Available from: 2015-10-21 Created: 2015-10-21 Last updated: 2018-06-07Bibliographically approved
Organisations

Search in DiVA

Show all publications