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  • 1. Andersson, Karin
    et al.
    Pokrzywa, M
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Inhibition of TTR aggregation-induced cell death: a new role for serum amyloid P component2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed)
    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.

  • 2.
    Khoshnood, Behzad
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Urm1: an essential regulator of JNK signaling and oxidative stress in Drosophila melanogaster2016In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 73, no 9, 1939-1954 p.Article in journal (Refereed)
    Abstract [en]

    Ubiquitin-related modifier 1 (Urm1) is a ubiquitin-like molecule (UBL) with the dual capacity to act both as a sulphur carrier and posttranslational protein modifier. Here we characterize the Drosophila melanogaster homologues of Urm1 (CG33276) and its E1 activating enzyme Uba4 (CG13090), and show that they function together to induce protein urmylation in vivo. Urm1 conjugation to target proteins in general, and to the evolutionary conserved substrate Peroxiredoxin 5 (Prx5) specifically, is dependent on Uba4. A complete loss of Urm1 is lethal in flies, although a small number of adult zygotic Urm1 (n123) mutant escapers can be recovered. These escapers display a decreased general fitness and shortened lifespan, but in contrast to their S. cerevisiae counterparts, they are resistant to oxidative stress. Providing a molecular explanation, we demonstrate that cytoprotective JNK signaling is increased in Urm1 deficient animals. In agreement, molecular and genetic evidence suggest that elevated activity of the JNK downstream target genes Jafrac1 and gstD1 strongly contributes to the tolerance against oxidative stress displayed by Urm1 (n123) null mutants. In conclusion, Urm1 is a UBL that is involved in the regulation of JNK signaling and the response against oxidative stress in the fruit fly.

  • 3.
    Noborn, Fredrik
    et al.
    Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden.
    O'Callaghan, Paul
    Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 751 85 Uppsala, Sweden.
    Hermansson, Erik
    Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Zhang, Xiao
    Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 751 85 Uppsala, Sweden.
    Ancsin, John B
    Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden.
    Damas, Ana M
    Molecular Structure Group, Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Presto, Jenny
    Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan
    Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Saraiva, Maria J
    Neurobiology Group, Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kisilevsky, Robert
    Department of Pathology and Molecular Medicine, Richardson Laboratory, 88 Stuart Street, Queen’s University, Kingston, ON, Canada K7L 3N6.
    Westermark, Per
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 751 85 Uppsala, Sweden.
    Li, Jin-Ping
    Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden.
    Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 14, 5584-5589 p.Article in journal (Refereed)
    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.

  • 4.
    Pokrzywa, Malgorzata
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Cantera, Rafael
    Dacklin, Ingrid
    Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Vestling, Monika
    Hultmark, Dan
    Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Ultrastructural studies of mutant human transthyretin aggregates in transgenic Drosophila melanogaster2006In: J. Neurogenet., Vol. 20, no 3-4, 203-204 p.Article in journal (Other academic)
  • 5.
    Pokrzywa, Malgorzata
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Misfolded transthyretin causes behavioral changes in a Drosophila model for transthyretin-associated amyloidosis.2007In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 26, no 4, 913-924 p.Article in journal (Refereed)
    Abstract [en]

    Familial amyloidotic polyneuropathy is an autosomal dominant neurodegenerative disorder caused by accumulation of mutated transthyretin (TTR) amyloid fibrils in different organs and prevalently around peripheral nerves. We have constructed transgenic flies, expressing the clinical amyloidogenic variant TTRL55P and the engineered variant TTR-A (TTRV14N/V16E) as well as the wild-type protein, all in secreted form. Within a few weeks, both mutants but not the wild-type TTR demonstrated a time-dependent aggregation of misfolded molecules. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability and shortened life span. In contrast, expression of wild-type TTR had no discernible effect on either longevity or behavior. These results suggest that Drosophila can be used as a disease-model to study TTR amyloid formation, and to screen for pharmacological agents and modifying genes.

  • 6.
    Pokrzywa, Malgorzata
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vestling, Monika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cantera, Rafael
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Uptake of aggregating transthyretin by fat body in a drosophila model for TTR-associated amyloidosis2010In: PloS one, ISSN 1932-6203, Vol. 5, no 12, e14343- p.Article in journal (Refereed)
    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.

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