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  • 51.
    Malisauskas, Mantas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zamotin, Vladimir
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Jass, Jana
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Noppe, Wim
    Dobson, Christopher M
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Amyloid protofilaments from the calcium-binding protein equine lysozyme: formation of ring and linear structures depends on pH and metal ion concentration2003Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 330, nr 4, s. 879-890Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The calcium-binding equine lysozyme has been found to undergo conversion into amyloid fibrils during incubation in solution at acidic pH. At pH 4.5 and 57 °C, where equine lysozyme forms a partially unfolded molten globule state, the protein forms protofilaments with a width of ca. 2 nm. In the absence of Ca2+ the protofilaments are present as annular structures with a diameter of 40–50 nm. In the presence of 10 mM CaCl2 the protofilaments of equine lysozyme are straight or curved; they can assemble into thicker threads, but they do not appear to undergo circularisation. At pH 2.0, where the protein is more destabilised compared to pH 4.5, fibril formation occurs at 37 °C and 57 °C. At pH 2.0, both ring-shaped and linear protofilaments are formed, in which periodic repeats of ca 35 nm can be distinguished clearly. The rings constitute about 10% of all fibrillar species under these conditions and they are characterised by a larger diameter of 70–80 nm. All the structures bind Congo red and thioflavine T in a manner similar to fibrils associated with a variety of amyloid diseases. At pH 2.0, fibril formation is accompanied by some acidic hydrolysis, producing specific fragmentation of the protein, leading to the accumulation of two peptides in particular, consisting of residues 1–80 and 54–125. At the initial stages of incubation, however, full-length equine lysozyme represents the dominant species within the fibrils. We propose that the ring-shaped structures observed here, and in the case of disease-associated proteins such as -synuclein, could be a second generic type of amyloid structure in addition to the more common linear fibrils.

  • 52. Minkevich, N. I.
    et al.
    Rakitina, T. V.
    Bogachuk, A. P.
    Radchenko, V. V.
    Surina, E. A.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yanamandra, Kiran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iomdina, E. N.
    Babichenko, I. I.
    Kostanyan, I. A.
    Lipkin, V. M.
    Formation of amyloid-like fibrillar structures and destruction of fibroblasts of the Tenon's capsule in progressive myopia due to resistance of the pigment epithelium-derived factor to restricted proteolysis2012Ingår i: Russian journal of bioorganic chemistry, ISSN 1068-1620, E-ISSN 1608-330X, Vol. 38, nr 6, s. 605-612Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that, normally, two forms of the pigment epithelium-derived factor (PEDF) with molecular weights of 50 and 45 kDa are present in the Tenon's capsule in equal amounts. These forms represent the full-length protein and a product of restricted proteolysis of PEDF. In persons with myopia, the full-length uncleaved factor was predominantly detected, which correlated with the disturbance of collagen fiber formation. An immunohistochemical study of the Tenon's capsule using polyclonal antibodies to PEDF showed that, in the control group, the factor is localized solely inside fibroblasts, whereas in patients with myopia, PEDF is distributed outside the cell as a halo around destroyed fibroblasts. It was shown in the present work using atomic force microscopy and immunodot assay with antibodies specific to amyloid fibrils that only the full-length PEDF is capable of forming amyloid-like fibrillar structures. The accumulation of fibrils leads to the destruction of fibroblasts and is a cause of changes in the biochemical composition and morphological structure of the Tenon's capsule in myopia.

  • 53. Minkevich, Natalya I.
    et al.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iomdina, Elena N.
    Rakitina, Tatiana V.
    Bogachuk, Anna P.
    Kakuev, Dmitry L.
    Smirnova, Evgeniya V.
    Babichenko, Igor I.
    Lipkin, Valery M.
    Abnormal pigment epithelium-derived factor processing in progressive myopia2016Ingår i: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 152, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pigment Epithelium-Derived Factor (PEDF) is a secreted glycoprotein belonging to the family of non inhibitory serpins. It is known, that in cases of complicated myopia, the content of PEDF in aqueous humor of the anterior chamber is significantly reduced. Here we examined a bulk of Tenon's capsule samples obtained from various groups of myopes, to examine PEDF processing in progressive myopia. We have analyzed the distribution of full length PEDF50 and its truncated form PEDF45 in the soluble and insoluble fractions extracted from Tenon's capsule of myopic and control (non-myopic) patients using SDS-polyacrylamide gel electrophoresis, as well as monitored the proteolytic degradation of PEDF ex vivo by enzyme-linked immunosorbent assay. These results were complemented by PEDF mRNA analysis in correspondent tissues by using qPCR and immunohistochemistry analysis of PEDF distribution in normal and myopic specimens. We found that in the Tenon's capsule of patients suffering from a high myopia the level of "soluble" 45 kDa PEDF reduced by 2-fold, while the content of "insoluble" 50 kDa form of PEDF was increased by 4-fold compared to controls. Excessive amount of PEDF50 in myopic specimens have been shown to correlate with the abrogated PEDF processing rather than with an increase of its expression. Moreover, immunohistochemical staining of the myopic Tenon's capsule tissue sections revealed the halo of deposited PEDF50 in the fibroblast extracellular space. These findings suggest that in myopia limited proteolysis of PEDF is altered or abrogated. Accumulation of full-length PEDF insoluble aggregates in the fibroblast intercellular space may affect cell survival and consequently causes the destructive changes in the extracellular matrix of the eye connective tissues. As a result, the abrogation of full-length PEDF normal processing can be an important mechanism leading to biomechanical destabilization of the scleral capsule and myopia progression.

  • 54.
    Morozova, Ludmilla A
    et al.
    Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford.
    Haynie, Donald T
    Arico-Muendel, Christopher
    Van Dael, Herman
    Dobson, Christopher M
    Structural basis of the stability of a lysozyme molten globule.1995Ingår i: Nature Structural Biology, ISSN 1072-8368, Vol. 2, nr 10, s. 871-875Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hydrogen exchange measurements on equine lysozyme show that amides in three of the four major helices of the native protein are significantly protected in a molten globule state formed at pH 2. The pattern of protection within the different helices, however, varies significantly. Examination of the pattern in the light of the native structure indicates that the side chains of the protected residues form a compact cluster within the core of the protein. We suggest that such a core is present in the molten globule state, indicating the existence of substantial native-like interactions between hydrophobic residues. The formation of clusters of this type during the early stages of folding could be crucial to directing polypeptide chains to their native structures.

  • 55.
    Morozova, Ludmilla
    et al.
    University of Leuven, Campus Kortrijk, IRC, Belgium.
    Haezebrouck, Petra
    Van Cauwelaert, Frans
    Stability of equine lysozyme: I. thermal unfolding behaviour1991Ingår i: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 41, nr 2, s. 185-191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The thermal denaturation of Ca(2+)- and apo-forms of equine lysozyme was followed by using far and near UV circular dichroism and intrinsic fluorescence methods. The difference found between the temperature dependence of the ellipticity at 222 nm and 287 nm, which show two stages in the thermal transition, and those at 228 nm and 294 nm, which indicate only one stage over a wide range of temperatures reflects that different subdivisions of the protein molecule are characterized by a different stability, cooperativity and pathway of denaturation. The first transition, reflected in the increase of the ellipticity at 222 nm and 287 nm, coincides with the transition detected by fluorescence and occurs at 30-50 degrees C for the apo-form and at 50-60 degrees C for the Ca(2+)-form of lysozyme. It seems to correlate with the transfer of some tryptophan residues to a more hydrophobic environment and with a local rearrangement of the tertiary and secondary structures. The unfolding transition detected by the decrease of the ellipticity at all wavelengths occurs nearly in the same temperature region for the apo- and Ca(2+)-forms, i.e. 50-80 degrees C and 55-80 degrees C, respectively. The presence of a Ca(2+)-binding loop in equine lysozyme may be partly responsible for the drastic destabilization of its structure as a whole both in the presence but especially in the absence of Ca2+ in comparison with hen and human lysozymes.

  • 56.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    ELOA complexes exert toxicity by targeting cullular membrance: Comparison with HAMLET2012Konferensbidrag (Övrigt vetenskapligt)
  • 57.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Equine lysozyme: the molecular basis of folding, self-assembly and innate amyloid toxicity.2007Ingår i: FEBS Letter, ISSN 0014-5793, Vol. 581, nr 14, s. 2587-92Artikel i tidskrift (Refereegranskat)
  • 58.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Physico-chemical mechanisms of amyloid formation-disaggregation: in vitro and in vivo studies2010Konferensbidrag (Refereegranskat)
  • 59.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Proinflammatory S100A8/A9 in amyloid formation in the aging prostate: risk factor for cancer2016Ingår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 38, s. S28-S28Artikel i tidskrift (Övrigt vetenskapligt)
  • 60.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pro-inflammatory S100a9 protein involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease serves as a robust biomarker differentiating early stages of dementia2017Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 284, s. 138-139Artikel i tidskrift (Övrigt vetenskapligt)
  • 61.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Strengthening the positions of Scandinavian science in research on neurodegenerative and age-dependent amyloid diseases2010Ingår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, nr 1, s. 39-Artikel i tidskrift (Refereegranskat)
  • 62.
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Protein misfolding and self-assembly: acquired functions and their therapeutic and pathological significance2010Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, nr 22, s. 4577-Artikel i tidskrift (Refereegranskat)
  • 63.
    Morozova-Roche, Ludmilla A
    et al.
    University of Oxford, Centre for Molecular Sciences, New Chemistry Laboratory.
    Arico-Muendel, C C
    Haynie, D T
    Emelyanenko, V I
    Van Dael, H
    Dobson, C M
    Structural characterisation and comparison of the native and A-states of equine lysozyme1997Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 268, nr 5, s. 903-921Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Native state 1H NMR resonance assignments for 125 of the 129 residues of equine lysozyme have enabled measurement of the hydrogen exchange kinetics for over 60 backbone amide and three tryptophan indole hydrogen atoms in the native state. Native holo equine lysozyme hydrogen exchange protection factors are as large as 10(6), the most protected residues being located in elements of secondary structure. High exchange protection in the domain interface correlates with the binding of Ca2+ in this region. Equine lysozyme differs from most non-Ca2+ binding lysozymes in forming a highly populated partially folded state at low pH. The protein in this A-state at pH 2.0 has been found to bind 1-anilino-naphthalene-8-sulphonate with the enhancement of fluorescent intensity and blue shift in the spectral maximum characteristic of molten globules. NMR spectra indicate that the A-state is globally much less ordered than native equine lysozyme but does not contain significant regions of random coil structure. The amides most protected against hydrogen exchange in the A-state (protection factors up to 10(2) at 5 degrees C) correspond to residues of three of the four alpha-helices of the native state; the side-chains of these residues form a hydrophobic cluster that includes five aromatic residues. Circular dichroism and tryptophan fluorescence indicate that these residues are substantially more constrained than similar residues in "classical" molten globules. Taken together, the data suggest a model for the A-state of equine lysozyme in which a more ordered core is surrounded by a less ordered but still compact polypeptide chain.

  • 64.
    Morozova-Roche, Ludmilla A
    et al.
    Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford.
    Jones, Jonathan A
    Noppe, Wim
    Dobson, Christopher M
    Independent nucleation and heterogeneous assembly of structure during folding of equine lysozyme1999Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 289, nr 4, s. 1055-1073Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The refolding of equine lysozyme from guanidinium chloride has been studied using hydrogen exchange pulse labelling in conjunction with NMR spectroscopy and stopped flow optical methods. The stopped flow optical experiments indicate that extensive hydrophobic collapse occurs rapidly after the initiation of refolding. Pulse labelling experiments monitoring nearly 50 sites within the protein have enabled the subsequent formation of native-like structure to be followed in considerable detail. They reveal that an intermediate having persistent structure within three of the four helices of the alpha-domain of the protein is formed for the whole population of molecules within 4 ms. Subsequent to this event, however, the hydrogen exchange protection kinetics are complex and highly heterogeneous. Analysis of the results by fitting to stretched exponential functions shows that a series of other intermediates is formed as a consequence of the stepwise assembly of independently nucleated local regions of structure. In some molecules the next step in folding involves the stabilisation of the remaining helix in the alpha-domain, whilst in others persistent structure begins to form in the beta-domain. The formation of native-like structure throughout the beta-domain is itself heterogeneous, involving at least three kinetically distinguishable steps. Residues in loop regions throughout the protein attain persistent structure more slowly than regions of secondary structure. There is in addition evidence for locally misfolded regions of structure that reorganise on much longer timescales. The results reveal that the native state of the protein is generated by the heterogeneous assembly of a series of locally cooperative regions of structure. This observation has many features in common with the findings of recent theoretical simulations of protein folding.

  • 65.
    Morozova-Roche, Ludmilla A
    et al.
    Oxford Centre for Molecular Sciences, New Chemistry Laboratory, University of Oxford.
    Zurdo, Jesús
    Spencer, Andrew
    Noppe, Wim
    Receveur, Veronique
    Archer, David B
    Joniau, Marcel
    Dobson, Christopher M
    Amyloid fibril formation and seeding by wild-type human lysozyme and its disease-related mutational variants2000Ingår i: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 130, nr 2-3, s. 339-351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wild-type human lysozyme and its two stable amyloidogenic variants have been found to form partially folded states at low pH. These states are characterized by extensive disruption of tertiary interactions and partial loss of secondary structure. Incubation of the proteins at pH 2.0 and 37 degrees C (Ile56Thr and Asp67His variants) or 57 degrees C (wild-type) results in the formation of large numbers of fibrils over several days of incubation. Smaller numbers of fibrils could be observed under other conditions, including neutral pH. These fibrils were analyzed by electron microscopy, Congo red birefringence, thioflavine-T binding, and X-ray fiber diffraction, which unequivocally show their amyloid character. These data demonstrate that amyloidogenicity is an intrinsic property of human lysozyme and does not require the presence of specific mutations in its primary structure. The amyloid fibril formation is greatly facilitated, however, by the introduction of "seeds" of preformed fibrils to the solutions of the variant proteins, suggesting that seeding effects could be important in the development of systemic amyloidosis. Fibril formation by wild-type human lysozyme is greatly accelerated by fibrils of the variant proteins and vice versa, showing that seeding is not specific to a given protein. The fact that wild-type lysozyme has not been found in ex vivo deposits from patients suffering from this disease is likely to be related to the much lower population of incompletely folded states for the wild-type protein compared to its amyloidogenic variants under physiological conditions. These results support the concept that the ability to form amyloid is a generic property of proteins, but one that is mitigated against in a normally functioning organism.

  • 66.
    Morozova-Roche, Ludmilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berliner, Lawrence J.
    Denver University.
    Permyakov, Eugene A.
    Institute for Biological Instrumentation of the Russian Academy of Sciences.
    Calcium-binding lysozymes2012Bok (Övrigt vetenskapligt)
    Abstract [en]

    In this book, the authors describe an important class of calcium binding lysozymes that are evolutionarily related to the lysozyme superfamily and the lactalbumins. The authors take the reader through a journey from the evolution, then the structure and properties of the calcium binding lysozymes. They discuss new unique protein folding pathways with local cooperative, close related folding modes that exhibit multiple folding pathways which are not properties of the lactalbumins or non calcium binding lysozymes. They comprise one of the most diverse group of examples in protein folding. In addition this protein class, especially equine lysozyme, shows peculiar amyloid assembly properties that are not common with other fibril forming proteins. It is one of the first shown to form ring shaped amyloids and other complexes in vitro. Lastly equine lysozyme forms complex with oleic acid, a unique form ELOA, which contributes to the family of the human and bovine lactalbumin analogs HAMLET and BAMLET.

  • 67.
    Morozova-Roche, Ludmilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Davis, Jason
    Institutionen för kemi, Oxford universitet, Storbritannien.
    Ny snabbanalys för diagnos av Parkinsons sjukdom2012Ingår i: Neurologi i Sverige, ISSN 2000-8538, nr 4, s. 74-78Artikel, forskningsöversikt (Övrigt vetenskapligt)
  • 68.
    Morozova-Roche, Ludmilla
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Malisauskas, Mantas
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    A false paradise - mixed blessings in the protein universe: the amyloid as a new challenge in drug development.2007Ingår i: Current Medicinal Chemistry, ISSN 0929-8673, Vol. 14, nr 11, s. 1221-30Artikel i tidskrift (Refereegranskat)
  • 69.
    Morozova-Roche, Ludmilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zamotin, Vladimir
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Malisauskas, Mantas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Öhman, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chertkova, Rita
    Lavrikova, Marika A
    Kostanyan, Irina A
    Dolgikh, Dmiltry A
    Kirpichnikov, Michail P
    Fibrillation of Carrier Protein Albebetin and Its Biologically Active Constructs. Multiple Oligomeric Intermediates and Pathways2004Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Biochemistry, Vol. 43, nr 30, s. 9610-9619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We showed that the genetically engineered carrier-protein albebetin and its biologically active constructs with interferon-2 octapeptide LKEKKYSP or differentiation factor hexapeptide TGENHR are inherently highly amyloidogenic at physiological pH. The kinetics of fibrillation were monitored by thioflavine-T (ThT) binding and the morphological changes by atomic force microscopy. Fibrillation proceeds via multiple pathways and includes a hierarchy of amyloid structures ranging from oligomers to protofilaments and fibrils. Comparative height and volume microscopic measurements allowed us to identify two distinct types of oligomeric intermediates: pivotal oligomers ca. 1.2 nm in height comprised of 10-12 monomers and on-pathway amyloid-competent oligomers ca. 2 nm in height constituted of 26-30 molecules. The former assemble into chains and rings with "bead-on-string morphology", in which a "bead" corresponds to an individual oligomer. Once formed, the rings and chains remain in solution simultaneously with fibrils. The latter give rise to protofilaments and fibrils, and their formation is concomitant with an increasing level of ThT binding. The amyloid nature of filamentous structures was confirmed by a pronounced ThT and Congo red binding and -sheet-rich far-UV circular dichroism. We suggest that transformation of the pivotal oligomers into the amyloid-prone ones is a limiting stage in amyloid assembly. Peptides, either fused to albebetin or added into solution, and an increased ionic strength promote fibrillation of albebetin (net charge of -12) by counterbalancing critical electrostatic repulsions. This finding demonstrates that the fibrillation of newly designed polypeptide-based products can produce multimeric amyloid species with a potentially "new" functionality, raising questions about their safety.

  • 70. Mossberg, Ann-Kristin
    et al.
    Hun Mok, Kenneth
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Svanborg, Catharina
    Structure and function of human α-lactalbumin made lethal to tumor cells (HAMLET)-type complexes2010Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, nr 22, s. 4614-4625Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human α-lactalbumin made lethal to tumor cells (HAMLET) and equine lysozyme with oleic acid (ELOA) are complexes consisting of protein and fatty acid that exhibit cytotoxic activities, drastically differing from the activity of their respective proteinaceous compounds. Since the discovery of HAMLET in the 1990s, a wealth of information has been accumulated, illuminating the structural, functional and therapeutic properties of protein complexes with oleic acid, which is summarized in this review. In vitro, both HAMLET and ELOA are produced by using ion-exchange columns preconditioned with oleic acid. However, the complex of human α-lactalbumin with oleic acid with the antitumor activity of HAMLET was found to be naturally present in the acidic fraction of human milk, where it was discovered by serendipity. Structural studies have shown that α-lactalbumin in HAMLET and lysozyme in ELOA are partially unfolded, 'molten-globule'-like, thereby rendering the complexes dynamic and in conformational exchange. HAMLET exists in the monomeric form, whereas ELOA mostly exists as oligomers and the fatty acid stoichiometry varies, with HAMLET holding an average of approximately five oleic acid molecules, whereas ELOA contains a considerably larger number (11- 48). Potent tumoricidal activity is found in both HAMLET and ELOA, and HAMLET has also shown strong potential as an antitumor drug in different in vivo animal models and clinical studies. The gain of new, beneficial function upon partial protein unfolding and fatty acid binding is a remarkable phenomenon, and may reflect a significant generic route of functional diversification of proteins via varying their conformational states and associated ligands.

  • 71. Musatov, Alexey
    et al.
    Permyakov, Eugine A
    Bagelova, J
    Morozova, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Snyrov, VL
    Some aspects of fluorescence and microcalorimetric studies of cytochrome C oxidase1990Ingår i: Biochemistry international, ISSN 0158-5231, Vol. 21, nr 3, s. 563-71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Effects of the solubilizing detergent type, pH and temperature on the structure of cytochrome c oxidase have been studied by the intrinsic fluorescence and scanning microcalorimetry methods. The data obtained allow to conclude that the enzyme solubilization by lauryl maltoside gives a more native preparation in comparison with that obtained by solubilization in Tween 80.

  • 72.
    Nielsen, Søren B
    et al.
    Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
    Wilhelm, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vad, Brian
    Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Otzen, Daniel
    Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
    The interaction of equine lysozyme: oleic acid complexes with lipid membranes suggests a cargo off-loading mechanism2010Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 398, nr 2, s. 351-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The normal function of equine lysozyme (EL) is the hydrolysis of peptidoglycan residues of bacterial cell walls. EL is closely related to alpha-lactalbumins with respect to sequence and structure and further possesses the calcium binding site of alpha-lactalbumins. Recently, EL multimeric complexes with oleic acids (ELOA) were shown to possess tinctorial and morphological properties, similar to amyloidal aggregates, and to be cytotoxic. ELOA's interactions with phospholipid membranes appears to be central to its biological action, similar to human alpha-lactalbumin made lethal to tumor cells (HAMLET). Here, we describe the interaction of ELOA with phospholipid membranes. Confocal scanning laser microscopy shows that ELOA, but not native EL, accumulates on the surface of giant unilamellar vesicles, without inducing significant membrane permeability. Quartz crystal microbalance with dissipation (QCM-D) data indicated an essentially non-disruptive binding of ELOA to supported lipid bilayers, leading to formation of highly dissipative and "soft" lipid membrane; at higher concentrations of ELOA, the lipid membrane desorbs from the surface probably as bilayer sheets of vesicles. This membrane rearrangement occurred to a similar extent when free oleic acid (OA) was added, but not when free OA was removed from ELOA by prior incubation with BSA, emphasizing the role of OA in this process. NMR data indicated an equilibrium between free and bound OA which shifts towards free OA as ELOA is progressively diluted indicating that OA is relatively loosely bound. Activity measurements together with fluorescence spectroscopy and circular dichroism suggested a conversion of ELOA toward a more native-like state on interaction with lipid membranes, although complete refolding was not observed. Altogether, these results suggest that ELOA may act as an OA carrier and facilitate OA transfer to the membrane. ELOA's properties illustrate that protein folding variants may possess specific functional properties distinct from the native protein. Abbreviations QCM-D, Quartz crystal microbalance with dissipation; CD, Circular dichroism; EL, equine lysozyme; ELOA, EL complex with oleic acid; OA, oleic acid, CSLM, Confocal scanning laser microscopy, Df, dissipation-frequency.

  • 73. Ostrovskaya, RU
    et al.
    Gruden, MA
    Bobkova, NA
    Sewell, RD
    Gudasheva, TA
    Samokhin, AN
    Seredinin, SB
    Noppe, W
    Sherstnev, VV
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.2007Ingår i: J Psyckopharmacol, Vol. 21, nr 6, s. 611-9Artikel i tidskrift (Refereegranskat)
  • 74.
    Pansieri, Jonathan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ostojic, Lucija
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iashchishyn, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Magzoub, Mazin
    Wallin, Cecilia
    Warmlander, Sebastian K. T. S.
    Graslund, Astrid
    Ngoc, Mai Nguyen
    Smirnovas, Vytautas
    Svedruzic, Zeljko
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs2019Ingår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, nr 7, s. 1410-1417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from A beta peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.

  • 75.
    Permyakov, E A
    et al.
    Institute of Biological Physics, Pushchino, Russia.
    Kalinichenko, L P
    Morozova, L A
    Institute of Biological Physics, Pushchino, Russia.
    Yarmolenko, V V
    Burstein, E A
    alpha-Lactalbumin binds magnesium ions: study by means of intrinsic fluorescence technique.1981Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 102, nr 1, s. 1-7Artikel i tidskrift (Refereegranskat)
  • 76. Permyakov, E A
    et al.
    Morozova, L A
    Institute of Biological Physics, Pushchino, Russia.
    Burstein, E A
    Cation binding effects on the pH, thermal and urea denaturation transitions in alpha-lactalbumin.1985Ingår i: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 21, nr 1, s. 21-31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The binding of monovalent (Na+, K+) and divalent (Ca2+, Mg2+) cations to bovine alpha-lactalbumin at 20 and 37 degrees C has been studied by means of intrinsic protein fluorescence. The values of apparent binding constants for these ions obtained at 37 degrees C are about one order of magnitude lower than those measured at 20 degrees C. Urea and alkali (pH greater than 10) induce unfolding transitions which involve stable partially unfolded intermediates for all metal ion-bound forms of alpha-lactalbumin. Heating induces similar partially unfolded states. Nevertheless, the partially unfolded states induced by heating, urea, alkaline or acidic treatments are somewhat different in their tryptophan residue environment properties. The results have been interpreted in terms of a simple scheme of equilibria between metal-free and metal-bound forms in their native, partially unfolded and unfolded states. The scheme provides an approach to the quantitative interpretation of any transition equilibrium shift induced by a low molecular mass species able to be bound by a protein.

  • 77.
    Permyakov, E A
    et al.
    Institute of Biological Physics, Pushchino, Russia.
    Morozova, L A
    Institute of Biological Physics, Pushchino, Russia.
    Kalinichenko, L P
    Derezhkov, V Yu
    Interaction of alpha-lactalbumin with Cu2+.1988Ingår i: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 32, nr 1, s. 37-42Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It has been shown by intrinsic fluorescence spectroscopy that alpha-lactalbumin has several Cu2+ -binding sites per molecule. The Ca2+ -loaded protein binds two or more Cu2+ per molecule with an association constant of about 3 X 10(3) M-1. Apo-alpha-lactalbumin binds one Cu2+ per molecule with association constant 8 X 10(4) M-1 and from two to three Cu2+ with an association constant of about 4 X 10(3) M-1. The results obtained from spectrofluorometric pH titration of alpha-lactalbumin in the acidic pH region show the possible involvement of histidine residues in the coordination of Cu2+. The binding of Cu2+ to alpha-lactalbumin lowers significantly its thermostability and stability towards urea denaturation. The stability of Cu2+, Ca2+-alpha-lactalbumin against thermal and urea denaturation is similar to that of the apo protein. The thermal transition in Cu2+, Ca2+-alpha-lactalbumin occurs within the region of physiological temperatures which may suggest the existence of some thermal regulation of its functioning in vivo.

  • 78. Permyakov, E A
    et al.
    Yarmolenko, V V
    Kalinichenko, L P
    Morozova, L A
    Institute of Biological Physics, Pushchino, Russia.
    Burstein, E A
    Calcium binding to alpha-lactalbumin: structural rearrangement and association constant evaluation by means of intrinsic protein fluorescence changes.1981Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 100, nr 1, s. 191-7Artikel i tidskrift (Refereegranskat)
  • 79.
    Permyakov, Eugene A.
    et al.
    (Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow region, Russia.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berliner, Lawrence J.
    Denver University, Denver, Colorado.
    Calcium Binding Lysozymes2012Bok (Övrigt vetenskapligt)
  • 80. Permyakov, Eugene A
    et al.
    Permyakov, Serge E
    Deikus, Gintaras Y
    Morozova-Roche, Ludmila A
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Grishchenko, Valery M
    Kalinichenko, Lina P
    Uversky, Vladimir N
    Ultraviolet illumination-induced reduction of alpha-lactalbumin disulfide bridges2003Ingår i: Proteins: Structure, Function, and Bioinformatics, Vol. 51, nr 4, s. 498-503Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prolonged exposure of Ca2+-loaded or Ca2+-depleted human -lactalbumin to ultraviolet light (270-290 nm, 1 mW/cm2, for 2 to 4 h) results in a 10-nm red shift of its tryptophan fluorescence spectrum. Gel chromatography of the UV-illuminated samples reveals two non-native protein forms: (1) a component with a red-shifted tryptophan fluorescence spectrum; and (2) a component with kynurenine-like fluorescent properties. The first component has from 0.6 to 0.9 free DTNB-reactive SH groups per protein molecule, which are absent in the native protein and is characterized by slightly lowered Ca2+-affinity (2 × 108 M-1 versus 8 × 108 M-1 for the native protein) and absence of observable thermal transition. The second component corresponds to the protein with photochemically modified tryptophan residues. It is assumed that the UV excitation of tryptophan residue(s) in -lactalbumin is followed by a transfer of electrons to the SS bonds, resulting in their reduction. Mass spectrometry data obtained for trypsin-fragmented UV-illuminated -lactalbumin with acrylodan-modified free thiol groups reveal the reduction of the 61-77 and 73-91 disulfide bridges. The effect observed has to be taken into account in any UV-region spectral studies of -lactalbumin. Proteins 2003;51:498-503.

  • 81. Permyakov, Sergei E
    et al.
    Khokhlova, Tatyana I
    Nazipova, Aliya A
    Zhadan, Andrey P
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Permyakov, Eugene A
    Calcium-binding and temperature induced transitions in equine lysozyme: new insights from the pCa-temperature "phase diagrams".2006Ingår i: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 65, nr 4, s. 984-98Artikel i tidskrift (Refereegranskat)
  • 82. Perálvarez-Marín, Alex
    et al.
    Mateos, Laura
    Zhang, Ce
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Singh, Shalini
    Cedazo-Mínguez, Angel
    Visa, Neus
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gräslund, Astrid
    Barth, Andreas
    Influence of residue 22 on the folding, aggregation profile, and toxicity of the Alzheimer's amyloid β peptide2009Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 97, nr 1, s. 277-285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid beta peptide involved in Alzheimer's disease. We focused our study on the Glu22 residue, comparing the effects of freshly prepared samples and samples aged for at least 20 days. In the aged samples, a high propensity for aggregation and beta-sheet secondary structure appears when residue 22 is capable of establishing polar (Glu22 in wild-type) or hydrophobic (Val22 in E22V) interactions. The Arctic variant (E22G) presents a mixture of mostly disordered and alpha-helix structures (with low beta-sheet contribution). Analysis of transmission electron micrographs and atomic force microscopy images of the peptide variants after aging showed significant quantitative and qualitative differences in the morphology of the formed aggregates. The effect on human neuroblastoma cells of these Abeta(12-28) variants does not correlate with the amount of beta-sheet of the aggregates. In samples allowed to age, the native sequence was found to have an insignificant effect on cell viability, whereas the Arctic variant (E22G), the E22V variant, and the slightly-aggregating control (F19G-F20G) had more prominent effects.

  • 83.
    Röhrig, Ursula
    et al.
    Max-Planck Institute, Department of Cell Biology, Martinsried, Germany.
    Gerisch, Günther
    Morozova, Ludmilla
    Max-Planck Institute, Department of Cell Biology, Martinsried, Germany.
    Schleicher, Michael
    Wegner, Albrecht
    Coactosin interferes with the capping of actin filaments1995Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 374, nr 2, s. 284-286Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Coactosin, a 16 kDa protein associated with the actin cytoskeleton from Dictyostelium discoideum, was purified by an improved method, in which other components of the cytoskeleton were removed. The highly purified coactosin had no effect on the time course of actin polymerization, but when added to actin in presence of capping proteins, coactosin counteracted the capping activity of these proteins. The capping proteins cap32/34 and severin domain 1 retarded actin polymerization, on addition of coactosin to samples containing one of these capping proteins the time course of actin polymerization became close to controls without capping proteins.

  • 84. Van Dael, Herman
    et al.
    Haezebrouck, Petra
    Morozova, Ludmilla
    Max Planck Institute fur Biochemie, Martinsried, Germany.
    Arico-Muendel, Christopher
    Dobson, Christopher M
    Partially folded states of equine lysozyme. Structural characterization and significance for protein folding.1993Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 32, nr 44, s. 11886-11894Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite their homologous structure, c-type lysozymes and alpha-lactalbumins have been found to differ profoundly in their unfolding behavior, in that the alpha-lactalbumins readily enter a partially unfolded collapsed state (the "molten globule"), whereas lysozymes unfold cooperatively to a highly unfolded state. The calcium-binding property of lysozyme from equine milk provides an evolutionary link between the two families of proteins. We demonstrate here that equine lysozyme undergoes a two-stage unfolding transition upon heating or in the presence of guanidine hydrochloride that is highly dependent on the state of calcium binding. Differential scanning calorimetry shows the two transitions to be particularly well resolved in the calcium-free protein, where the first transition occurs with a midpoint at 44 degrees C at pH 4.5 or in 0.8 M GdnHCl at pH 7.5, 25 degrees C, and the second occurs near 70 degrees C at pH 4.5 or in 3.7 M GdnHCl at pH 7.5, 25 degrees C. In the presence of calcium, the first transition takes place with a midpoint of 55 degrees C or in excess of 2.5 M GdnHCl, but the parameters for the second transition remain unchanged. Fluorescence emission and UV difference absorption spectroscopy suggest that the first transition generates an intermediate state in which sequestration of some aromatic side chains from solvent has occurred whereas the second represents denaturation to a highly unfolded state. CD and 1H NMR results indicate that the intermediate state possesses extensive secondary and tertiary structure, although the latter is substantially disordered.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 85. Vetri, Valeria
    et al.
    Leone, Maurizio
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vestergaard, Bente
    Fodera, Vito
    Unlocked Concanavalin A Forms Amyloid-like Fibrils from Coagulation of Long-lived "Crinkled'' Intermediates2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 7, s. e68912-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding the early events during amyloid aggregation processes is crucial to single out the involved molecular mechanisms and for designing ad hoc strategies to prevent and reverse amyloidogenic disorders. Here, we show that, in conditions in which the protein is positively charged and its conformational flexibility is enhanced, Concanavalin A leads to fibril formation via a non-conventional aggregation pathway. Using a combination of light scattering, circular dichroism, small angle X-ray scattering, intrinsic (Tryptophan) and extrinsic (ANS) fluorescence and confocal and 2-photon fluorescence microscopy we characterize the aggregation process as a function of the temperature. We highlight a multi-step pathway with the formation of an on-pathway long-lived intermediate and a subsequent coagulation of such "crinkled'' precursors into amyloid-like fibrils. The process results in a temperature-dependent aggregation-coagulation pathway, with the late phase of coagulation determined by the interplay between hydrophobic and electrostatic forces. Our data provide evidence for the complex aggregation pathway for a protein with a highly flexible native conformation. We demonstrate the possibility to generate a long-lived intermediate whose proportion and occurrence are easily tunable by experimental parameters (i.e. temperature). As a consequence, in the case of aggregation processes developing through well-defined energy barriers, our results can open the way to new strategies to induce more stable in vitro on-pathway intermediate species through a minute change in the initial conformational flexibility of the protein. This will allow isolating and experimentally studying such transient species, often indicated as relevant in neurodegenerative diseases, both in terms of structural and cytotoxic properties.

  • 86.
    Vogl, Thomas
    et al.
    Institute of Immunology, University of Muenster, Germany.
    Gharibyan, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes2012Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 13, nr 3, s. 2893-2917Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+ and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation.

  • 87.
    Vukojevic, Vladana
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
    Bowen, Alice M
    Department of Chemistry, University of Oxford, Physical and Theoretical Chemistry Laboratory, Oxford OX1 3QZ, U.K..
    Wilhelm, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ming, Yu
    Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hore, PJ
    Department of Chemistry, University of Oxford, Physical and Theoretical Chemistry Laboratory, Oxford OX1 3QZ, U.K..
    Terenius, Lars
    Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ce, Zhang
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lipoprotein complex of equine lysozyme with oleic acid (ELOA) interactions with the plasma membrane of live cells2010Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, nr 18, s. 14782-14787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent evidence supports the idea that early aggregates, protein, and lipoprotein oligomers but not large aggregates like fibrils that are formed at late stages of the aggregation process are responsible for cytotoxicity. Oligomers can interact with the cellular plasma membrane affecting its structure and/or dynamics or may be taken up by the cells. In either case, disparate cascades of molecular interactions are activated in the attempt to counteract the disturbance induced by the oligomers. If unsuccessful, cell death follows. Here, we study the molecular and cellular mechanisms underlying PC12 cell death caused by ELOA oligomers. ELOA, a lipoprotein complex formed by equine lysozyme (EL) and oleic acid (OA), induces cell death in all tested cell lines, but the actual mechanism of its action is not known. We have used methods with single-molecule sensitivity, fluorescence correlation spectroscopy (FCS), fluorescence cross-correlation spectroscopy (FCCS), and confocal laser scanning microscopy (CLSM) imaging by avalanche photodiodes (APD), so-called APD imaging, to study ELOA interactions with the plasma membrane in live PC12 cells. We detected ELOA accumulation in the cell surroundings, observed ELOA interactions with the plasma membrane, and local changes in plasma membrane lipid dynamics in the vicinity of ELOA complexes. These interactions resulted in plasma membrane rupture, followed by rapid influx and distribution of ELOA inside the already dead cell. In order to probe the ELOA−plasma membrane interaction sites at the molecular and atomic levels, the ELOA complexes were further studied by photochemically induced dynamic nuclear polarization (photo-CIDNP) spectroscopy, nuclear magnetic resonance (NMR) and atomic force microscopy (AFM). We observed a novel mechanism of oligomer toxicity−cell death induced by continuous disturbance of the plasma membrane, eventually causing permanent plasma membrane damage and identified the sites in ELOA that are potentially involved in the interactions with the plasma membrane.

  • 88.
    Vukojevic, Vladana
    et al.
    Department of Clinical Neuroscience, Karolinska Institute.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Structural origin of ELOA toxicity: implication for HAMLET-type protein complexes with oleic acid2012Ingår i: Lipoproteins - Role in Health and Diseases / [ed] Sasa Frank and Gerhard Kostner, InTech, 2012, s. 663-674Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 89.
    Wang, Chao
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iashchishyn, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kara, John
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Fodera, Vito
    Vetri, Valeria
    Sancataldo, Giuseppe
    Marklund, Niklas
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model2019Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 699, s. 199-205Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post- TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochemistry we have shown that S100A9 was produced by both neuronal and microglial cells. However, A beta peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously observed in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and atomic force microscopy we demonstrated that in vitro S100A9 self- assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temperature and reduction/oxidation, which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.

  • 90.
    Wang, Chao
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iashchishyn, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nyström, Sofie
    Klementieva, Oxana
    Kara, John
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bengtsson, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Foderà, Vito
    Vetri, Valeria
    Sancataldo, Giuseppe
    Horvath, Istvan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Moskalenko, Roman
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Pathology, Sumy State University, Sumy, Ukraine.
    Rofougaran, Reza
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Wang, Mingde
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Gouras, Gunnar
    Marklund, Niklas
    Shankar, S.K.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    S100A9-driven amyloid-neuroinflammatory cascade in traumatic brain injury as a risk factor for Alzheimer’s diseaseManuskript (preprint) (Övrigt vetenskapligt)
  • 91.
    Wang, Chao
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iashchishyn, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of General Chemistry, Sumy State University, Sumy, 40000, Ukraine.
    Pansieri, Jonathan
    Nyström, Sofie
    Klementieva, Oxana
    Kara, John
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Horvath, Istvan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Moskalenko, Roman
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Pathology, Sumy State University, Sumy, 40000, Ukraine.
    Rofougaran, Reza
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gouras, Gunnar
    Kovacs, Gabor G.
    Shankar, S. K.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 12836Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

  • 92.
    Wang, Chao
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Klechikov, Alexey G.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gharibyan, Anna L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Jarvet, Jüri
    Zhao, Lina
    Jia, Xueen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shankar, S. K.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Mu, Yuguang
    Gräslund, Astrid
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade2014Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, nr 4, s. 507-522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with A beta. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with A beta and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling A beta protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with A beta, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and A beta. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate A beta aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.

  • 93.
    Wilhelm, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Darinskas, A
    Noppe, W
    Duchardt, E
    Mok, KH
    Vukojevic, V
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Protein oligomerization induced by oleic acid at the solidliquid interface: equine lysozyme cytotoxic complexes2009Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, nr 15, s. 3975-3989Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein oligomeric complexes have emerged as a major target of current research because of their key role in aggregation processes in living systems and in vitro. Hydrophobic and charged surfaces may favour the self-assembly process by recruiting proteins and modifying their interactions. We found that equine lysozyme assembles into multimeric complexes with oleic acid (ELOA) at the solid–liquid interface within an ion-exchange chromatography column preconditioned with oleic acid. The properties of ELOA were characterized using NMR, spectroscopic methods and atomic force microscopy, and showed similarity with both amyloid oligomers and the complexes with oleic acid and its structural homologous protein α-lactalbumin, known as humanα-lactalbumin made lethal for tumour cells (HAMLET). As determined by NMR diffusion measurements, ELOA may consist of 4–30 lysozyme molecules. Each lysozyme molecule is able to bind 11–48 oleic acids in various preparations. Equine lysozyme acquired a partially unfolded conformation in ELOA, as evident from its ability to bind hydrophobic dye 8-anilinonaphthalene-1-sulfonate. CD and NMR spectra. Similar to amyloid oligomers, ELOA also interacts with thioflavin-T dye, shows a spherical morphology, assembles into ring-shaped structures, as monitored by atomic force microscopy, and exerts a toxic effect in cells. Studies of well-populated ELOA shed light on the nature of the amyloid oligomers and HAMLET complexes, suggesting that they constitute one large family of cytotoxic proteinaceous species. The hydrophobic surfaces can be used profitably to produce complexes with very distinct properties compared to their precursor proteins.

  • 94.
    Wilhelm, Kristina R
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yanamandra, Kiran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gruden, M A
    P.K. Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia.
    Zamotin, V
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Malisauskas, M
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Casaite, V
    Department of Molecular Microbiology and Biotechnology, Institute of Biochemistry, Vilnius, Lithuania.
    Darinskas, A
    Institute of Immunology, Vilnius University, Vilnius, Lithuania.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients2007Ingår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 14, nr 3, s. 327-334Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral immune responses can be sensitive indicators of disease pathology. We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of 26 Parkinson's disease (PD) patients compared with controls by using ELISA. We found a statistically significant increase of the autoimmune responses to both antigens in PD patients compared with controls with a mean increase of 70% and 50% in the autoimmune reactions towards insulin and S100B, respectively. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in PD patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type, while sequential epitope of native insulin is hidden within the amyloid structures. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

  • 95. Williamson, Philip T. F.
    et al.
    Horrocks, Jack
    Maheswaran, Luckshi
    Concistre, Maria
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Unravelling the Role of S100A9 in the Development of Neurodegenerative Disease2019Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, nr 3, s. 338A-338AArtikel i tidskrift (Övrigt vetenskapligt)
  • 96. Xu, Weixin
    et al.
    Zhang, Ce
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Derreumaux, Philippe
    Graslund, Astrid
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mu, Yuguang
    Intrinsic determinants of A beta(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 9, s. e24329-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The propensity of amyloid-beta (A beta) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment A beta(12-24) and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of A beta(12-24) dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, beta-sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in A beta(12-24) amyloid formation; it is highly prompted in the order of pH 5.0 > 2.9 > > 8.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of beta-sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases.

  • 97.
    Xu, Weixin
    et al.
    East China Normal University, Shanghai, China.
    Zhang, Ce
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zhang, John Z H
    East China Normal University, Shanghai, China.
    Mu, Yuguang
    School of Biological Sciences, Nanyang Technological University, Singapore.
    pH-Dependent Conformational Ensemble and Polymorphism of Amyloid-beta Core Fragment2013Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, nr 28, s. 8392-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Characterization of amyloid oligomeric species is important due to its possible responsibility for the toxicity of amyloid proteins, whereas it is difficult to detect by current spectroscopic techniques. The pH-dependent tetramerization and fibrillation of the central hydrophobic segment of Alzheimer amyloid β-peptide (Aβ(12-24)) were respectively explored by all-atom replica exchange molecular dynamics simulations and by fluorescence and atomic force microscopy measurements. Our combined study shows that more β-sheet structures in the early event of tetramerization is linked directly to the high propensity to form amyloid fibrils in the consequent fibrillation. Both tetramerization and fibrillation are strongly regulated by pH. At pH 5.0, Aβ(12-24) has two opposite terminal charges. The electrostatic attraction between the side-chains of His13/His14 and Glu22/Asp23 thus acts as a "pattern keeper", resulting in high propensity of amyloid formation. These results suggest that pH effects most likely by affecting the ionization properties of the Aβ(12-24) peptide. Specifically, the pH-dependent equilibrium conformational distribution of different aggregate species are well-investigated in detail. Our findings also give hints to other experimental findings that the kinetics and morphologies of Aβ fibril formation are strongly pH-dependent.

  • 98.
    Yanamandra, Kiran
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Alexeyev, Oleg
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zamotin, Vladimir
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Srivastava, Vaibhav
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Shchukarev, Andrey
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brorsson, Ann-Christin
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
    Tartaglia, Gian Gaetano
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
    Vogl, Thomas
    Institute of Immunology, University of Münster, Münster, Germany.
    Kayed, Rakez
    Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
    Wingsle, Gunnar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Olsson, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Dobson, Christopher M
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Elgh, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate2009Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, nr 5, s. e5562-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The conversion of soluble peptides and proteins into polymeric amyloid structures is a hallmark of many age-related degenerative disorders, including Alzheimer's disease, type II diabetes and a variety of systemic amyloidoses. We report here that amyloid formation is linked to another major age-related phenomenon - prostate tissue remodelling in middle-aged and elderly men.

    Methodology/Principal Findings By using multidisciplinary analysis of corpora amylacea inclusions in prostate glands of patients diagnosed with prostate cancer we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. In prostate protease rich environment the amyloids are stabilized by dystrophic calcification and lateral thickening. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro under native and acidic conditions and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions.

    Conclusions/Significance These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate. The results provide strong support for the prediction that the generic ability of polypeptide chains to convert into amyloids could lead to their involvement in an increasing number of otherwise apparently unrelated diseases, particularly those associated with ageing.

  • 99.
    Yanamandra, Kiran
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gruden, Marina A
    Institute of Normal Physiology, Moscow.
    Casaite, Vida
    Institute of Biochemistry, Vilnius .
    Meskys, Rolandas
    Institute of Biochemistry, Vilnius .
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Alpha-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson's Disease Patients2011Ingår i: PLoS One, ISSN 1932-6203, Vol. 6, nr 4, s. e18513-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments.

    Methodology/Principal Findings

    Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies – α-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance. We found significantly higher antibody levels towards monomeric α-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001). This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards α-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001). Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Aβ (1–40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration.

    Conclusions/Significance

    Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein – α-synuclein can be of value in the development of treatment and diagnostic strategies, especially during the early disease stages.

  • 100.
    Zamotin, Vladimir
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gharibyan, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gibanova, NV
    Lavrikova, MA
    Dolgikh, DA
    Kirpichnikov, MP
    Kostanyan, IA
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cytotoxicity of albebetin oligomers depends on cross-beta-sheet formation2006Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, nr 10, s. 2451-2457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prefibrillar cytotoxicity was suggested as a common amyloid characteristic. We showed two types of albebetin prefibrillar oligomers are formed during incubation at pH 7.3. Initial round-shaped oligomers consist of 10–15 molecules determined by atomic force microscopy, do not bind thioflavin-T and do not affect viability of granular neurons and SH-SY5Y cells. They are converted into ca. 30–40-mers possessing cross-β-sheet and reducing viability of neuronal cells. Neither monomers nor fibrils possess cytotoxicity. We suggest that oligomeric size is important for stabilising cross-β-sheet core critical for cytotoxicity. As albebetin was used as a carrier-protein for drug delivery, examination of amyloidogenicity is required prior polypeptide biomedical applications.

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