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Lundgren, Erik
Publications (10 of 26) Show all publications
Suhr, O. B., Lundgren, E. & Westermark, P. (2017). One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition. Journal of Internal Medicine, 281(4), 337-347
Open this publication in new window or tab >>One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition
2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 4, p. 337-347Article, review/survey (Refereed) Published
Abstract [en]

Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full-length TTR, whereas the other, type B, consists only of full-length TTR. All organs of an individual patient contain ATTR deposits of either type A or type B fibrils, and the composition in each individual remains unchanged over time. The finding of two distinct types of ATTR fibrils suggests that there are at least two different pathways in operation for ATTR fibril formation. For the most common European mutation, TTR Val30Met, ATTR fibril composition is related to the outcome of liver transplantation, which is the first successful treatment for the disease, and the penetrance of the trait. In addition, the presence of C-terminal ATTR fragments has an impact on the affinity for various tracers used for noninvasive imaging of amyloid depositions such as 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy and positron emission tomography utilizing Pittsburgh component B, and even for the gold standard diagnostic procedure, tissue biopsy stained by Congo red and examined under polarized light. The importance of amyloid fibril composition needs to be taken into consideration when designing clinical trials of treatment modalities, and also in the evaluation of diagnostic methods such as imaging techniques.

Keywords
amyloid cardiac hypertrophy, amyloid neuropathy, familial amyloidosis, pathology, therapeutics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-131030 (URN)10.1111/joim.12585 (DOI)000397490100002 ()28093848 (PubMedID)
Available from: 2017-02-02 Created: 2017-02-02 Last updated: 2018-06-09Bibliographically approved
Andersson, K., Pokrzywa, M., Dacklin, I. & Lundgren, E. (2013). Inhibition of TTR aggregation-induced cell death: a new role for serum amyloid P component. PLoS ONE, 8(2)
Open this publication in new window or tab >>Inhibition of TTR aggregation-induced cell death: a new role for serum amyloid P component
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Serum amyloid P component (SAP) is a glycoprotein that is universally found associated with different types of amyloid deposits. It has been suggested that it stabilizes amyloid fibrils and therefore protects them from proteolytic degradation.

METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we show that SAP binds not only to mature amyloid fibrils but also to early aggregates of amyloidogenic mutants of the plasma protein transthyretin (TTR). It does not inhibit fibril formation of TTR mutants, which spontaneously form amyloid in vitro at physiological pH. We found that SAP prevents cell death induced by mutant TTR, while several other molecules that are also known to decorate amyloid fibrils do not have such effect. Using a Drosophila model for TTR-associated amyloidosis, we found a new role for SAP as a protective factor in inhibition of TTR-induced toxicity. Overexpression of mutated TTR leads to a neurological phenotype with changes in wing posture. SAP-transgenic flies were crossed with mutated TTR-expressing flies and the results clearly confirmed a protective effect of SAP on TTR-induced phenotype, with an almost complete reduction in abnormal wing posture. Furthermore, we found in vivo that binding of SAP to mutated TTR counteracts the otherwise detrimental effects of aggregation of amyloidogenic TTR on retinal structure.

CONCLUSIONS/SIGNIFICANCE: Together, these two approaches firmly establish the protective effect of SAP on TTR-induced cell death and degenerative phenotypes, and suggest a novel role for SAP through which the toxicity of early amyloidogenic aggregates is attenuated.

Keywords
Serum amyloid P component, transthyretin, familial amyloid polyneuropathy, cell death, neuroblastoma, drosophila
National Category
Cell and Molecular Biology
Research subject
Molecular Biology; Medical Cell Biology
Identifiers
urn:nbn:se:umu:diva-65622 (URN)10.1371/journal.pone.0055766 (DOI)000314691100067 ()
Note

Epub 2013 Feb 4.

Available from: 2013-02-09 Created: 2013-02-09 Last updated: 2018-06-08Bibliographically approved
Noborn, F., O'Callaghan, P., Hermansson, E., Zhang, X., Ancsin, J. B., Damas, A. M., . . . Li, J.-P. (2011). Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein. Proceedings of the National Academy of Sciences of the United States of America, 108(14), 5584-5589
Open this publication in new window or tab >>Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein
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2011 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 14, p. 5584-5589Article in journal (Refereed) Published
Abstract [en]

Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a Drosophila model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.

National Category
Cell and Molecular Biology
Research subject
biology
Identifiers
urn:nbn:se:umu:diva-46262 (URN)10.1073/pnas.1101194108 (DOI)21422279 (PubMedID)
Available from: 2011-08-29 Created: 2011-08-29 Last updated: 2018-06-08Bibliographically approved
Blomberg, J., Höglund, A., Eriksson, D., Ruuth, K., Jacobsson, M., Nilsson, J. & Lundgren, E. (2011). Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line. Apoptosis (London), 16(8), 783-794
Open this publication in new window or tab >>Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line
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2011 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 16, no 8, p. 783-794Article in journal (Refereed) Published
Abstract [en]

Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.

Keywords
Apoptosis, Death receptor, Resistance, Fas, Interferon, cFLIP
National Category
Biophysics Cell and Molecular Biology Medical and Health Sciences Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-3478 (URN)10.1007/s10495-011-0606-0 (DOI)
Available from: 2008-09-22 Created: 2008-09-22 Last updated: 2018-06-09Bibliographically approved
Suhr, O. B., Lundgren, E. & Westermark, P. (2010). Transthyretin amyloidoses: new strategies for therapeutic intervention. Drugs of the future, 35(4), 325-332
Open this publication in new window or tab >>Transthyretin amyloidoses: new strategies for therapeutic intervention
2010 (English)In: Drugs of the future, ISSN 0377-8282, E-ISSN 2013-0368, Vol. 35, no 4, p. 325-332Article in journal (Refereed) Published
Abstract [en]

Liver transplantation as a treatment for transthyretin amyloidosis (ATTR) was introduced 20 years ago and is currently the only available treatment for the disease. Although the procedure has been proven to halt the progression of the disease for most patients, several unexpected complications have emerged, and it is obvious that for several mutations liver transplantation has no impact on the progression of the disease. Heart complications, especially in elderly patients, have been a cause of concern for many patients, including those with the most widespread neuropathic mutation, transthyretin (TTR)Val30Met. These drawbacks and the risk involved with transplantation, together with the need for life-long immunosuppressive therapy, have demonstrated the need for an effective medical treatment. From the experience with liver transplant patients, it appears that the amyloidogenic properties of wild-type TTR are enhanced once amyloid formation has started, and that elimination of the mutated TTR is not sufficient to prevent further amyloid formation in all cases. The development of animal models for the disease has further increased our understanding of factors involved in amyloid formation, and offers the possibility to test new medical treatment modalities. From our experience with liver transplantation, it appears that treatment directed towards stabilizing the TTR tetramer, eliminating misfolded TTR, decreasing TTR serum concentrations, decreasing toxicity and removing amyloid deposits are the most attractive modalities for treatment. Several studies are currently planned or ongoing to explore these possibilities, and promising results are already being reported.

Keywords
protein-a amyloidosis, transgenic mouse model
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-43199 (URN)10.1358/dof.2010.035.04.1452076 (DOI)000279519200006 ()
Available from: 2011-04-22 Created: 2011-04-22 Last updated: 2018-06-08Bibliographically approved
Pokrzywa, M., Dacklin, I., Vestling, M., Hultmark, D., Lundgren, E. & Cantera, R. (2010). Uptake of aggregating transthyretin by fat body in a drosophila model for TTR-associated amyloidosis. PloS one, 5(12), e14343
Open this publication in new window or tab >>Uptake of aggregating transthyretin by fat body in a drosophila model for TTR-associated amyloidosis
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2010 (English)In: PloS one, ISSN 1932-6203, Vol. 5, no 12, p. e14343-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A functional link has been established between the severe neurodegenerative disorder Familial amyloidotic polyneuropathy and the enhanced propensity of the plasma protein transthyretin (TTR) to form aggregates in patients with single point mutations in the TTR gene. Previous work has led to the establishment of an experimental model based on transgenic expression of normal or mutant forms of human TTR in Drosophila flies. Remarkably, the severity of the phenotype was greater in flies that expressed a single copy than with two copies of the mutated gene.

METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyze the distribution of normal and mutant TTR in transgenic flies, and the ultrastructure of TTR-positive tissues to clarify if aggregates and/or amyloid filaments are formed. We report the formation of intracellular aggregates of 20 nm spherules and amyloid filaments in thoracic adipose tissue and in brain glia, two tissues that do not express the transgene. The formation of aggregates of nanospherules increased with age and was more considerable in flies with two copies of mutated TTR. Treatment of human neuronal cells with protein extracts prepared from TTR flies of different age showed that the extracts from older flies were less toxic than those from younger flies.

CONCLUSIONS/SIGNIFICANCE: These findings suggest that the uptake of TTR from the circulation and its subsequent segregation into cytoplasmic quasi-crystalline arrays of nanospherules is part of a mechanism that neutralizes the toxic effect of TTR.

Identifiers
urn:nbn:se:umu:diva-38857 (URN)10.1371/journal.pone.0014343 (DOI)000285381200003 ()21179560 (PubMedID)
Available from: 2011-01-04 Created: 2011-01-04 Last updated: 2018-06-08Bibliographically approved
Sundström, P., Nyström, M., Ruuth, K. & Lundgren, E. (2009). Antibodies to specific EBNA-1 domains and HLA DRB1*1501 interact as risk factors for multiple sclerosis.. Journal of Neuroimmunology, 215(1-2), 102-107
Open this publication in new window or tab >>Antibodies to specific EBNA-1 domains and HLA DRB1*1501 interact as risk factors for multiple sclerosis.
2009 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 215, no 1-2, p. 102-107Article in journal (Refereed) Published
Abstract [en]

Epitope reactivity of multiple sclerosis (MS) plasma antibodies against the Epstein-Barr virus protein EBNA-1 and its association with HLA DRB1*1501 status was investigated in a case-referent study. Based on EBNA-1 fragment reactivity and the effect of peptide blocking, four 29-36 amino acid long EBNA-1 fragments were selected for detailed studies. MS cases had increased antibody reactivity against several EBNA-1 domains, of which antibodies against EBNA-1 (amino acid 385-420) in HLA DRB1*1501 positive individuals were associated with a 24-fold risk increase for MS. The data need confirmation in a larger sample but suggest a role for this epitope in the autoimmune pathogenesis of MS.

Keywords
Multiple sclerosis; Epstein–Barr virus; EBNA-1; Autoimmune diseases; HLA; Case control studies
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32858 (URN)10.1016/j.jneuroim.2009.08.004 (DOI)19733917 (PubMedID)
Available from: 2010-03-29 Created: 2010-03-29 Last updated: 2018-06-08Bibliographically approved
Ericzon, B.-G., Lundgren, E. & Suhr, O. B. (2009). Liver Transplantation for Transthyretin Amyloidosis. In: Dr. Samantha J. Richardson, Dr. Vivian Cody (Ed.), Recent Advances in Transthyretin Evolution, Structure and Biological Functions: (pp. 239-260). New York: Springer Berlin/Heidelberg
Open this publication in new window or tab >>Liver Transplantation for Transthyretin Amyloidosis
2009 (English)In: Recent Advances in Transthyretin Evolution, Structure and Biological Functions / [ed] Dr. Samantha J. Richardson, Dr. Vivian Cody, New York: Springer Berlin/Heidelberg, 2009, p. 239-260Chapter in book (Other academic)
Abstract [en]

Liver transplantation has until now proved to be the only treatment available that halts the progression of hereditary transthyretin (TTR) associated amyloidosis. The rationale behind the procedure is to replace the liver producing variant TTR with one that produces wild type TTR only, and thereby cease the production of amyloidogenic TTR (ATTR). Even though the transplantation does not improve the patient's symptoms, the progression of the disease comes to a halt for a majority of patients. However, unforeseen complications after the transplantation have emerged, in particular a continuous amyloid formation in the heart observed in non-ATTR Val30Met mutations. Thus, combined liver and heart transplantation has been performed in selected cases. Since the ATTR liver functions normally apart from a synthesis of the variant TTR, utilisation of ATTR-amyloid patients' livers for transplantation of liver disease patients has been performed. In a few patients, development of amyloid disease has been reported, but the procedure remains an important source of organs, especially for patients with hepatocellular cancer.

Place, publisher, year, edition, pages
New York: Springer Berlin/Heidelberg, 2009
Keywords
Transthyretin, Liver transplantation, Heart complication, Amyloidosis
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-76163 (URN)10.1007/978-3-642-00646-3_15 (DOI)000272520300016 ()978-3-642-00645-6 (ISBN)978-3-642-00646-3 (ISBN)
Available from: 2013-07-05 Created: 2013-07-04 Last updated: 2018-06-08Bibliographically approved
Blomberg, J., Ruuth, K., Jacobsson, M., Höglund, A., Nilsson, J. A. & Lundgren, E. (2009). Reduced FAS transcription in clones of U937 cells that have acquired resistance to Fas-induced apoptosis. The FEBS Journal, 276(2), 497-508
Open this publication in new window or tab >>Reduced FAS transcription in clones of U937 cells that have acquired resistance to Fas-induced apoptosis
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2009 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no 2, p. 497-508Article in journal (Refereed) Published
Abstract [en]

Susceptibility to cell death is a prerequisite for the elimination of tumour cells by cytotoxic immune cells, chemotherapy or irradiation. Activation of the death receptor Fas is critical for the regulation of immune cell homeostasis and efficient killing of tumour cells by apoptosis. To define the molecular changes that occur during selection for insensitivity to Fas-induced apoptosis, a resistant variant of the U937 cell line was established. Individual resistant clones were isolated and characterized. The most frequently observed defect in the resistant cells was reduced Fas expression, which correlated with decreased FAS transcription. Clones with such reduced Fas expression also displayed partial cross-resistance to tumour necrosis factor-alpha stimulation, but the mRNA expression of tumour necrosis factor receptors was not decreased. Reintroduction of Fas conferred susceptibility to Fas but not to tumour necrosis factor-alpha stimulation, suggesting that several alterations could be present in the clones. The reduced Fas expression could not be explained by mutations in the FAS coding sequence or promoter region, or by silencing through methylations. Protein kinase B and extracellular signal-regulated kinase, components of signalling pathways downstream of Ras, were shown to be activated in some of the resistant clones, but none of the three RAS genes was mutated, and experiments using chemical inhibitors could not establish that the activation of these proteins was the cause of Fas resistance as described in other systems. Taken together, the data illustrate that Fas resistance can be caused by reduced Fas expression, which is a result of an unidentified mode of regulation.

Keywords
CpG methylation, ERK activation by PD98059, Fas, Fas expression, TNF-a Fas expression, TNF-a
National Category
Medical and Health Sciences Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32859 (URN)10.1111/j.1742-4658.2008.06790.x (DOI)19076218 (PubMedID)
Available from: 2010-03-29 Created: 2010-03-29 Last updated: 2018-06-08Bibliographically approved
Strannegård, O., Thorén, F. B. & Lundgren, E. (2008). [Interferon-alpha can improve the prognosis in high-risk melanoma. Combination of surgery, cytostatics and natural IFN-alpha doubled the survival rate.]. Läkartidningen, 105(6), 358-361
Open this publication in new window or tab >>[Interferon-alpha can improve the prognosis in high-risk melanoma. Combination of surgery, cytostatics and natural IFN-alpha doubled the survival rate.]
2008 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 6, p. 358-361Article in journal (Refereed) Published
Abstract [en]

Adjuvant behandling av melanom i stadium 2b–3 (högriskmelanom) med interferon-alfa (IFN-a) har i tidigare studier visat sig ge en fördröjning av sjukdomsprogressionen. Ingen studie har dock, oavsett typ av behandling, visat någon säkerställd långsiktig överlevnadsvinst vid melanom.

Verkningsmekanismen för effekten av IFN-a förefaller i första hand vara beroende av förmågan hos IFN-a att kraftfullt stimulera cellförmedlat immunsvar.

I en studie där adjuvansterapin utgjordes av sekventiell behandling med ett cytostatikum följt av naturligt IFN-a (som har ett flertal olika immunologiska effekter och är mindre benäget än rekombinant IFN-a att ge upphov till terapiresistens) fördubblades den långsiktiga överlevnadsfrekvensen hos patienter med högriskmelanom.

Place, publisher, year, edition, pages
Läkartidningen Förlag AB, 2008
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-20776 (URN)18380352 (PubMedID)
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2018-06-09Bibliographically approved
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