Anders Olofsson - Assistant Professor

Amyloid Fibrils and Cytotoxic Oligomers

Amyloidosis denotes a pathological condition characterized by fibrillar deposition of proteins and peptides. Up to date more than 25 human disorders have been linked to formation of amyloid. The fibrillar depositions may accumulate locally or systemic and depending on the associated protein as well as site of deposition, it can result in many different symptoms. The overall aim with our work is to understand the mechanism by which native, endogenous, polypeptides transforms into a pathological assembly and further to develop means for intervention. We focus on the complete chain of events spanning from a monomeric polypeptide to mature amyloid with a specific focus on the intermediate formation of oligomeric assemblies. Our established techniques involve recombinant expression and purification of proteins and peptides, CD, fluorescence, NMR, AFM, SPR, X-ray as well as immunological techniques. Moreover, using cell-based system for analysis of viability, correlations between structural properties and cytotoxic propensity can be made. Our work is focused on Familial Amyloidosis with Polyneuropathy as well as Alzheimer’s and Parkinson’s disease.

Alzheimer's disease (AD) is fatal disorder linked self-assembly of the amyloid-β peptide (Aβ) that ultimately forms fibrillar plaques (amyloid) within the brain of affected individuals. We focus on a structural and mechanistic understanding of Aβ fibril formation, including the effect of both intrinsic properties of the peptide as well as environmental factors influencing the process of Aβ self-assembly. It’s today well known that the cognitive impairment and synaptic dysfunction, characterising AD, better correlates with small and soluble Aβ-assemblies denoted oligomers. Detection of oligomers is today a difficult task. We therefore also focus on the development of improved detection methods, which have a translational impact on both diagnostics and therapeutic efforts.

Parkinsons disease (PD) belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. The underlying cause of PD is aggregation of a protein called α-synuclein that forms intracellular aggregates known as inclusion bodies. In analogy to Aβ α-synuclein forms both fibrils as well as oligomers having a potent cytotoxic effect. We focus both on structural and mechanistic explanations to the aggregating properties of α-synuclein as well as means to modulate and intervene the aggregation process.

Familial Amyloidotic Polyneuropathy (FAP) denotes a hereditary disorder associated with mutations in the plasma protein transthyretin (TTR). FAP displays an increased prevalence within the northern part of Sweden and is locally known as “Skelleftesjukan”. TTR forms a systemic form of amyloidosis but where depositions is localised predominantly to kidney, intestine, peripheral nerves and the heart. The clinical symptoms presents as sensory and motory dysfunction as well as heart problems. TTR is also associated with a senile form where the normal non-mutated variant forms amyloid deposits, predominantly localised to the heart which affect twenty five percent of all individuals above eighty years of age. We focus on an in depth understanding of the cytotoxic properties of TTR and its correlation to stability with a particular focus on thermodynamic and kinetic properties with the aim to develop novel and improved strategies for intervention.
 

Group members:
Irina Iakovleva (PhD student)
Kristoffer Brännström (Post Doc)

Publications

43: The N-terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH Through a Gain of Function Mechanism. Kristoffer Brännström, Anders Öhman, Lina Nilsson, Mathias Pihl, Linda Sandblad and Anders Olofsson. J Am Chem Soc. 2014 Aug 6.

42: Interaction studies of the human and Arabidopsis thaliana Med25-ACID proteins with the herpes simplex virus VP16- and plant-specific Dreba2a transcription factors. Ximena Aguilar, Jeanette Blomberg, Kristoffer Brännström, Anders Olofsson, Jürgen Schleucher and Stefan Björklund. PLoS One. 2014 May 29.

41: Transthyretin is dysregulated in preeclampsia and its native form prevents the onset of disease in mice. Satyan S Kalkunte, Stefan Neubeck, Wendy E Norris,1 Stefan Kostadinov, Dang Vu Hoang, Aftab Ahmed, Ferdinand von Eggeling, Zahir Shaikh, James Padbury, Göran Berg, Anders Olofsson, Udo R Markert and Surendra Sharma. Am J Pathol. 2013 Sep 10.

40. Horvath I, Sellstedt M, Weise C, Nordvall LM, Krishna Prasad G, Olofsson A,
Larsson G, Almqvist F, Wittung-Stafshede P. Modulation of α-synuclein fibrillization by ring- fused 2-pyridones: Templation and inhibition involve oligomers with different structure. Arch Biochem Biophys. 2013 Apr 15, 532(2):84-90 .

39. Ådén, Jörgen; Weise, Christoph; Brännström, Kristoffer; Olofsson, Anders; Wolf-Watz, Magnus. Structural topology and activation of an initial adenylate kinase-substrate complex. Biochemistry 2013 Feb 12;52(6):1055-61.

38: Kristoffer Brännström1, Anders Öhman2, Malin Lindhagen-Persson1 and Anders Olofsson. Ca2+ Enhances Aβ Polymerization Rate and Fibrillar Stability in a Dynamic Manner. Biochemical Journal 2012 Nov 22: 450:189-197

37: Hammer ND, McGuffie BA, Zhou Y, Badtke MP, Reinke AA, Brännström K, Gestwicki JE, Olofsson A, Almqvist F, Chapman MR. The C-Terminal Repeating Units of CsgB Direct Bacterial Functional Amyloid Nucleation. J Mol Biol. 2012 Sep 21;422(3):376-89. Epub 2012 Jun 7.

36: Brännström K, Ohman A, von Pawel Rammingen U, Olofsson A, Brattsand M. Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis. Biol Chem. 2012 Apr 1;393(5):369-77.

35: Blomberg J, Aguilar X, Brännström K, Rautio L, Olofsson A, Wittung-Stafshede P, Björklund S. Interactions between DNA, transcriptional regulator Dreb2a and the Med25 mediator subunit from Arabidopsis thaliana involve conformational changes. Nucleic Acids Res. 2012 Jul 1;40(13):5938-50. Epub 2012 Mar 24.

34: Horvath I, Weise CF, Andersson EK, Chorell E, Sellstedt M, Bengtsson C, Olofsson A, Hultgren SJ, Chapman M, Wolf-Watz M, Almqvist F, Wittung-Stafshede P. Mechanisms of protein oligomerization: inhibitor of functional amyloids templates α-synuclein fibrillation. J Am Chem Soc. 2012 Feb 22;134(7):3439-44. Epub 2012 Feb 9.

33: Treusch S, Hamamichi S, Goodman JL, Matlack KE, Chung CY, Baru V, Shulman JM, Parrado A, Bevis BJ, Valastyan JS, Han H, Lindhagen-Persson M, Reiman EM, Evans DA, Bennett DA, Olofsson A, DeJager PL, Tanzi RE, Caldwell KA, Caldwell GA, Lindquist S. Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. Science. 2011 Dec 2;334(6060):1241-5. Epub 2011 Oct 27.

32: Jia X, Gharibyan AL, Öhman A, Liu Y, Olofsson A, Morozova-Roche LA.
Neuroprotective and nootropic drug noopept rescues α-synuclein amyloid
cytotoxicity. J Mol Biol. 2011 Dec 16;414(5):699-712. Epub 2011 Oct 1.

31: Brännström K, Ohman A, Olofsson A. Aβ peptide fibrillar architectures
controlled by conformational constraints of the monomer. PLoS One. 2011;6(9):e25157. Epub 2011 Sep 29.

30: Ouberai M, Brannstrom K, Vestling M, Olofsson A, Dumy P, Chierici S, Garcia J. Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds. Org Biomol Chem. 2011 Feb 21;9(4):1140-7. Epub 2010 Dec 10.

29: Lindhagen-Persson M, Brännström K, Vestling M, Steinitz M, Olofsson A. Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies. PLoS One. 2010 Nov 10;5(11):e13928.

28: Mikhalyov I, Olofsson A, Gröbner G, Johansson LB. Designed fluorescent probes reveal interactions between amyloid-beta(1-40) peptides and GM1 gangliosides in micelles and lipid vesicles. Biophys J. 2010 Sep 8;99(5):1510-9.

27: Olofsson A, Lindhagen-Persson M, Vestling M, Sauer-Eriksson AE, Ohman A. Quenched hydrogen/deuterium exchange NMR characterization of amyloid-beta peptide aggregates formed in the presence of Cu2+ or Zn2+. FEBS J. 2009 Aug;276(15):4051-60.

26: Lundberg E, Olofsson A, Westermark GT, Sauer-Eriksson AE. Stability and fibril formation properties of human and fish transthyretin, and of the
Escherichia coli transthyretin-related protein. FEBS J. 2009 Apr;276(7):1999-2011.

25: Olofsson A, Sauer-Eriksson AE, Ohman A. Amyloid fibril dynamics revealed by combined hydrogen/deuterium exchange and nuclear magnetic resonance. Anal Biochem. 2009 Feb 15;385(2):374-6.

24: Lindhagen-Persson M, Vestling M, Reixach N, Olofsson A. Formation of
cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form. Amyloid. 2008 Dec;15(4):240-5.

23: Byström R, Aisenbrey C, Borowik T, Bokvist M, Lindström F, Sani MA, Olofsson A, Gröbner G. Disordered proteins: biological membranes as two-dimensional aggregation matrices. Cell Biochem Biophys. 2008;52(3):175-89. Epub 2008 Oct 31. Review.

22: Olofsson A, Borowik T, Gröbner G, Sauer-Eriksson AE. Negatively charged phospholipid membranes induce amyloid formation of medin via an alpha-helical intermediate. J Mol Biol. 2007 Nov 16;374(1):186-94. Epub 2007 Sep 5.

21: Olofsson A, Lindhagen-Persson M, Sauer-Eriksson AE, Ohman A. Amide solvent protection analysis demonstrates that amyloid-beta(1-40) and amyloid-beta(1-42) form different fibrillar structures under identical conditions. Biochem J. 2007 May 15;404(1):63-70.

20: Olofsson A, Sauer-Eriksson AE, Ohman A. The solvent protection of alzheimer amyloid-beta-(1-42) fibrils as determined by solution NMR spectroscopy. J Biol Chem. 2006 Jan 6;281(1):477-83.

19: Karlsson A, Olofsson A, Eneqvist T, Sauer-Eriksson AE. Cys114-linked dimers of transthyretin are compatible with amyloid formation. Biochemistry. 2005 Oct 4;44(39):13063-70.

18: Aberg V, Norman F, Chorell E, Westermark A, Olofsson A, Sauer-Eriksson AE, Almqvist F. Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of Abeta-peptide aggregation inhibitors. Org Biomol Chem. 2005 Aug 7;3(15):2817-23. Epub 2005 Jun 29.

17: Hörnberg A, Hultdin UW, Olofsson A, Sauer-Eriksson AE. The effect of iodide and chloride on transthyretin structure and stability. Biochemistry. 2005 Jul 5;44(26):9290-9.

16: Hörnberg A, Olofsson A, Eneqvist T, Lundgren E, Sauer-Eriksson AE. The beta-strand D of transthyretin trapped in two discrete conformations. Biochim Biophys Acta. 2004 Jul 1;1700(1):93-104.

15: Olofsson A, Ippel JH, Wijmenga SS, Lundgren E, Ohman A. Probing solvent accessibility of transthyretin amyloid by solution NMR spectroscopy. J Biol Chem. 2004 Feb 13;279(7):5699-707. Epub 2003 Nov 6.

14: Olofsson A, Ostman J, Lundgren E. Amyloid: morphology and toxicity. Clin Chem Lab Med. 2002 Dec;40(12):1266-70.

13: Eneqvist T, Olofsson A, Ando Y, Miyakawa T, Katsuragi S, Jass J, Lundgren E, Sauer-Eriksson AE. Disulfide-bond formation in the transthyretin mutant Y114C prevents amyloid fibril formation in vivo and in vitro. Biochemistry. 2002 Nov 5;41(44):13143-51.

12: Ippel JH, Olofsson A, Schleucher J, Lundgren E, Wijmenga SS. Probing solvent accessibility of amyloid fibrils by solution NMR spectroscopy. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8648-53. Epub 2002 Jun 18.

11: Andersson K, Olofsson A, Nielsen EH, Svehag SE, Lundgren E. Only
amyloidogenic intermediates of transthyretin induce apoptosis. Biochem Biophys Res Commun. 2002 Jun 7;294(2):309-14.

10: Olofsson A, Ippel HJ, Baranov V, Hörstedt P, Wijmenga S, Lundgren E. Capture of a dimeric intermediate during transthyretin amyloid formation. J Biol Chem. 2001 Oct 26;276(43):39592-9. Epub 2001 Aug 22.

9: Palha JA, Moreira P, Olofsson A, Lundgren E, Saraiva MJ. Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidotic polyneuropathy. J Mol Med. 2001;78(12):703-7.

8: Eneqvist T, Andersson K, Olofsson A, Lundgren E, Sauer-Eriksson AE. The beta-slip: a novel concept in transthyretin amyloidosis. Mol Cell. 2000
Nov;6(5):1207-18.

7: Redondo C, Damas AM, Olofsson A, Lundgren E, Saraiva MJ. Search for
intermediate structures in transthyretin fibrillogenesis: soluble tetrameric
Tyr78Phe TTR expresses a specific epitope present only in amyloid fibrils. J Mol Biol. 2000 Dec 1;304(3):461-70.

6: Hörnberg A, Eneqvist T, Olofsson A, Lundgren E, Sauer-Eriksson AE. A
comparative analysis of 23 structures of the amyloidogenic protein transthyretin. J Mol Biol. 2000 Sep 22;302(3):649-69.

5: Lundgren E, Persson H, Andersson K, Olofsson A, Dacklin I, Goldsteins G. Mapping protein conformations in fibril structures using monoclonal antibodies. Methods Enzymol. (book chapter) 1999;309:591-605.

4: Ando Y, Ando E, Ohlsson PI, Olofsson A, Sandgren O, Suhr O, Terazaki H, Obayashi K, Lundgren E, Ando M, Negi A. Analysis of transthyretin amyloid fibrils from vitreous samples in familial amyloidotic polyneuropathy (Val30Met). Amyloid. 1999 Jun;6(2):119-23.

3: Goldsteins G, Persson H, Andersson K, Olofsson A, Dacklin I, Edvinsson A, Saraiva MJ, Lundgren E. Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3108-13. PubMed PMID: 10077645;

2: Suhr OB, Ando Y, Ohlsson PI, Olofsson A, Andersson K, Lundgren E, Ando M, Holmgren G. Investigation into thiol conjugation of transthyretin in hereditary transthyretin amyloidosis. Eur J Clin Invest. 1998 Aug;28(8):687-92

1: Goldsteins G, Andersson K, Olofsson A, Dacklin I, Edvinsson A, Baranov V, Sandgren O, Thylén C, Hammarstrom S, Lundgren E. Characterization of two highly amyloidogenic mutants of transthyretin. Biochemistry. 1997 May 6;36(18):5346-52.


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Anders Olofsson

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Umeå University
Medical Biochemistry and Biophysics
SE-901 87 Umeå, SWEDEN 

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