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Ådén, Jörgen
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Publications (10 of 31) Show all publications
Näsström, T., Ådén, J., Shibata, F., Andersson, P. O. & Karlsson, B. C. .. (2020). A Capped Peptide of the Aggregation Prone NAC 71-82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations. International Journal of Molecular Sciences, 21(5), Article ID 1629.
Open this publication in new window or tab >>A Capped Peptide of the Aggregation Prone NAC 71-82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations
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2020 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 21, no 5, article id 1629Article in journal (Refereed) Published
Abstract [en]

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), misfolded α-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein have been limited so far, probably due to the fast aggregation kinetics and burial of aggregation prone segments in final cross-β-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid β-component (NAC) 71-82 amino acid stretch of α-synuclein demonstrated an increased aggregation propensity resulting in a cross-β-structure that is also found in prion proteins. From this, it was suggested that capped NAC 71-82 peptide oligomers would provide interesting motifs with a capacity to regulate disease development. Here, we demonstrated, from a series of circular dichroism spectroscopic measurements and molecular dynamics simulations, the molecular-environment-sensitive behaviour of the capped NAC 71-82 peptide in a solution phase and the formation of β-sheet oligomeric structures in the supernatant of a fibrillisation mixture. These results highlighted the use of the capped NAC 71-82 peptide as a motif in the preparation of oligomeric β-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
Thioflavin T fluorescence, capped NAC 71–82 peptide, circular dichroism spectroscopy, molecular dynamics simulations, soluble β-sheet oligomers, α-synuclein
National Category
Biophysics Biochemistry and Molecular Biology Other Basic Medicine Structural Biology Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-168812 (URN)10.3390/ijms21051629 (DOI)32120928 (PubMedID)
Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-03-11Bibliographically approved
Ådén, J., Ul Mushtaq, A., Dingeldein, A. P. G., Wallgren, M. & Gröbner, G. (2020). A novel recombinant expression and purification approach for the full-length anti-apoptotic membrane protein Bcl-2. Protein Expression and Purification, 172, Article ID 105628.
Open this publication in new window or tab >>A novel recombinant expression and purification approach for the full-length anti-apoptotic membrane protein Bcl-2
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2020 (English)In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 172, article id 105628Article in journal (Refereed) Published
Abstract [en]

Programmed cell death (apoptosis) is an essential mechanism in life that tightly regulates embryogenesis and removal of harmful cells. Besides an extrinsic pathway, an intrinsic (mitochondrial) apoptotic pathway exists where mitochondria are actively involved in cellular clearance in response to internal stress signals. Pro-apoptotic (death) and anti-apoptotic (survival) members of the B cell CLL/lymphoma-2 (Bcl-2) protein family meet at the mitochondrion's surface where they accurately regulate apoptosis. Overexpression of the anti-apoptotic Bcl-2 protein is a hallmark for many types of cancers and in particular for many treatment resistant tumors. Bcl-2 is a membrane protein residing in the mitochondrial outer membrane. Due to its typical membrane protein features including very limited solubility, it is difficult to express and to purify. Therefore, most biophysical and structural studies have used truncated, soluble versions. However, to understand its membrane-coupled function and structure, access to sufficient amount of full-length human Bcl-2 protein is a necessity. Here, we present a novel, E. coli based approach for expression and purification of preparative amounts of the full-length human isoform 2 of Bcl-2 (Bcl-2(2)), solubilized in detergent micelles, which allows for easy exchange of the detergent.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Apoptosis, Pro-survival Bcl-2 protein, High-yield expression, Full-length membrane protein, Detergent exchange
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biochemistry and Molecular Biology Cell Biology Biophysics
Identifiers
urn:nbn:se:umu:diva-169249 (URN)10.1016/j.pep.2020.105628 (DOI)
Available from: 2020-03-27 Created: 2020-03-27 Last updated: 2020-04-02Bibliographically approved
Alam, A., Golovliov, I., Javed, E., Kumar, R., Ådén, J. & Sjöstedt, A. (2020). Dissociation between the critical role of ClpB of Francisella tularensis for the heat shock response and the DnaK interaction and its important role for efficient type VI secretion and bacterial virulence. PLoS Pathogens, 16(4)
Open this publication in new window or tab >>Dissociation between the critical role of ClpB of Francisella tularensis for the heat shock response and the DnaK interaction and its important role for efficient type VI secretion and bacterial virulence
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2020 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 16, no 4Article in journal (Refereed) Epub ahead of print
Abstract [en]

Author summary Type VI secretion systems (T6SSs) are essential virulence determinants of many Gram-negative pathogens, including Francisella tularensis. This highly virulent bacterium encodes an atypical T6SS lacking ClpV, the ATPase crucial for prototypic T6SS sheath disassembly. It, however, possesses ClpB, a protein critical for heat shock survival via its interaction with DnaK. Since ClpB possesses ATPase activity, it has been hypothesized to provide a compensatory function for the absence of ClpV, a hypothesis supported by the recent findings from us and others. Here, we investigated how F. tularensis ClpB controls T6S. In silico modelling of the ClpB-DnaK complex identified key interactions that were experimentally verified. For example, mutating one of the DnaK-interacting residues rendered the bacterium exquisitely susceptible to heat shock, but had no effect on T6S and virulence. In contrast, removing the N-terminal of ClpB only had a slight effect on the heat shock response, but strongly compromised both T6S and virulence. Intriguingly, the Escherichia coli ClpB could fully complement the function of F. tularensis ClpB. The data demonstrate that the two critical roles of ClpB, mediating heat shock survival and effective T6S, are dissociated and that the N-terminal is crucial for T6S and virulence.

Place, publisher, year, edition, pages
Public Library of Science, 2020
National Category
Structural Biology Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biophysics
Identifiers
urn:nbn:se:umu:diva-170333 (URN)10.1371/journal.ppat.1008466 (DOI)
Available from: 2020-05-04 Created: 2020-05-04 Last updated: 2020-05-05
Ådén, J., Ul Mushtaq, A., Sparrman, T., Dingeldein, A. P., Wacklin, H. P., Wacklin, H., . . . Gröbner, G. (2020). Mitochondrial Membranes Involved in Apoptosis: the Bcl-2 Proteins. Paper presented at 64th Annual Meeting of the Biophysical-Society, FEB 15-19, 2020, San Diego, CA. Biophysical Journal, 118(3), 394A-394A
Open this publication in new window or tab >>Mitochondrial Membranes Involved in Apoptosis: the Bcl-2 Proteins
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2020 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 118, no 3, p. 394A-394AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Cell Press, 2020
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-169079 (URN)10.1016/j.bpj.2019.11.2242 (DOI)000513023202469 ()
Conference
64th Annual Meeting of the Biophysical-Society, FEB 15-19, 2020, San Diego, CA
Note

Supplement: 1

Meeting Abstract: 1934-Pos

Available from: 2020-03-23 Created: 2020-03-23 Last updated: 2020-03-23Bibliographically approved
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
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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
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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
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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, 21, 6946-6950
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
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2019 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 21, p. 6946-6950Article in journal (Refereed) Published
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)000485089300073 ()31419146 (PubMedID)2-s2.0-85071698867 (Scopus ID)
Available from: 2019-08-30 Created: 2019-08-30 Last updated: 2019-11-13Bibliographically approved
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
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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
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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
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